4-imidazolyl substituted pyrimidine derivatives with CDK inhibitory activity

ABSTRACT

Compounds of the formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5  and p are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.

This application is a 371 of PCT/GB03/00935 filed Mar. 6, 2003.

The invention relates to pyrimidine derivatives, or pharmaceuticallyacceptable salts or in vivo hydrolysable esters thereof, which possesscell-cycle inhibitory activity and are accordingly useful for theiranti-cell-proliferation (such as anti-cancer) activity and are thereforeuseful in methods of treatment of the human or animal body. Theinvention also relates to processes for the manufacture of saidpyrimidine derivatives, to pharmaceutical compositions containing themand to their use in the manufacture of medicaments of use in theproduction of an anti-cell-proliferation effect in a warm-blooded animalsuch as man.

A family of intracellular proteins called cyclins play a central role inthe cell cycle. The synthesis and degradation of cyclins is tightlycontrolled such that their level of expression fluctuates during thecell cycle. Cyclins bind to cyclin-dependent serine/threonine kinases(CDKs) and this association is essential for CDK (such as CDK1, CDK2,CDK4 and/or CDK6) activity within the cell. Although the precise detailsof how each of these factors combine to regulate CDK activity is poorlyunderstood, the balance between the two dictates whether or not the cellwill progress through the cell cycle.

The recent convergence of oncogene and tumour suppressor gene researchhas identified regulation of entry into the cell cycle as a key controlpoint of mitogenesis in tumours. Moreover, CDKs appear to be downstreamof a number of oncogene signalling pathways. Disregulation of CDKactivity by upregulation of cyclins and/or deletion of endogenousinhibitors appears to be an important axis between mitogenic signallingpathways and proliferation of tumour cells.

Accordingly it has been recognised that an inhibitor of cell cyclekinases, particularly inhibitors of CDK2, CDK4 and/or CDK6 (whichoperate at the S-phase, G1-S and G1-S phase respectively) should be ofvalue as a selective inhibitor of cell proliferation, such as growth ofmammalian cancer cells.

The present invention is based on the discovery that certain pyrimidinecompounds surprisingly inhibit the effects of cell cycle kinases showingselectivity for CDK2, CDK4 and CDK6, and thus possessanti-cell-proliferation properties. Such properties are expected to beof value in the treatment of disease states associated with aberrantcell cycles and cell proliferation such as cancers (solid tumours andleukemias), fibroproliferative and differentiative disorders, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl;wherein R² may be optionally substituted on carbon by one or morehydroxy, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; andwherein if said heterocyclyl contains an —NH— moiety that nitrogen maybe optionally substituted by one or more methyl, ethyl, acetyl,2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is substituted methyl, optionally substituted C₂₋₄alkyl,C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein saidsubstituents are selected from one or more hydroxy, methoxy, ethoxy,propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy, phenyl, methylamino, ethylamino, dimethylamino,diethylamino, methylthio, ethylthio, propylthio, isopropylthio,methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl,methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl orcyclopropylmethoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine;or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

According to a further feature of the present invention there isprovided a compound of formula (I) (as depicted above) wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl;wherein R² may be optionally substituted on carbon by one or moremethyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; andwherein if said heterocyclyl contains an —NH— moiety that nitrogen maybe optionally substituted by one or more methyl, ethyl, acetyl,2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl or optionallysubstituted C₂₋₆alkenyl; wherein said substituents are selected from oneor more methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy or cyclopropylmethoxy; or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof; provided thatthe compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

According to a further feature of the present invention there isprovided a compound of formula (I) (as depicted above) wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl;wherein R² may be optionally substituted on carbon by one or moremethyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; andwherein if said heterocyclyl contains an —NH— moiety that nitrogen maybe optionally substituted by one or more methyl, ethyl, acetyl,2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl,C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein saidsubstituents are selected from one or more hydroxy, methoxy, ethoxy,propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy orcyclopropylmethoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl”, “C₂₋₆alkyl”, “C₁₋₄alkyl” and “C₁₋₃alkyl” includepropyl, isopropyl and t-butyl. However, references to individual alkylgroups such as ‘propyl’ are specific for the straight chained versiononly and references to individual branched chain alkyl groups such as‘isopropyl’ are specific for the branched chain version only. A similarconvention applies to other radicals, for example“C₃₋₆cycloalkylC₁₋₃alkyl” includes cyclopropylmethyl, 1-cyclobutylethyland 3-cyclopropylpropyl. The term “halo” refers to fluoro, chloro, bromoand iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,monocyclic ring containing 4-6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, and a ring sulphur atom may beoptionally oxidised to form the S-oxide(s). Examples and suitable valuesof the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, thienyl, thiadiazolyl, piperazinyl,thiazolidinyl, thiomorpholino, pyrrolinyl, tetrahydropyranyl,tetrahydrofuryl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl andisoxazolyl. Suitably a “heterocyclyl” is tetrahydrofuryl.

Examples of “C₁₋₃alkoxy” include, methoxy, ethoxy and propoxy. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₄alkynyl” are ethynyl, 1-propynyl and 2-propynyl.Examples of “C₃₋₆cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Examples of “heterocyclylC₁₋₃alkyl” includepyridylmethyl, 3-morpholinopropyl and 2-pyrimid-2-ylethyl. Examples of“C₁₋₆alkoxyC₁₋₆alkyl” and “C₁₋₄alkoxyC₁₋₄alkyl” are methoxymethyl,2-methoxyethyl and 2-ethoxypropyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess CDK inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess CDK inhibitory activity. In particularthe skilled reader will appreciate that when R⁴ is hydrogen, theimidazole ring as drawn in formula (I) may tautomerise.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess CDK inhibitory activity.

Suitable values of R¹, R², R³, R⁴, R⁵ and p are as follows. Such valuesmay be used where appropriate with any of the definitions, claims orembodiments defined hereinbefore.

R¹ is fluoro, chloro, cyano, methyl, ethyl, methoxy or ethoxy.

p is 0.

p is 1.

p is 2; wherein the values of R¹ may be the same or different.

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl orheterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted oncarbon by one or more methyl, methoxy, ethoxy, trifluoromethyl.

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl orheterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy, ethoxy, trifluoromethyl.

R₂ is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may beoptionally substituted on carbon by one or more hydroxy, methoxy, ethoxyor trifluoromethyl.

R² is methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl, cyclobutyl,cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R² may beoptionally substituted on carbon by one or more methyl, methoxy, ethoxy,trifluoromethyl.

R² is methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl, cyclobutyl,cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R² may beoptionally substituted on carbon by one or more methoxy, ethoxy,trifluoromethyl.

R² is hydrogen, methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl,cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R²may be optionally substituted on carbon by one or more hydroxy, methoxy,ethoxy, trifluoromethyl.

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl,3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl,cyclopropylmethyl or tetrahydrofur-2-ylmethyl.

R² is hydrogen, 2-ethoxyethyl, 2-methoxyethyl, 2-hydroxyethyl,2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl,cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl.

R³ is hydrogen.

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl.

R⁴ is C₁₋₆alkyl.

R⁴ is C₁₋₄alkyl.

R⁴ is methyl, ethyl, isopropyl or 1-methoxyprop-2-yl.

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl.

R⁵ is substituted methyl or optionally substituted C₂₋₆alkyl; whereinsaid substituents are selected from one or more methoxy.

R⁵ is substituted methyl, C₃₋₆cycloalkyl, optionally substitutedC₂₋₆alkenyl or optionally substituted C₂₋₆alkyl; wherein saidsubstituents are selected from one or more methoxy or hydroxy.

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl,C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein saidsubstituents are selected from one or more hydroxy, methoxy, ethoxy,isopropoxy, phenyl, ethylamino, dimethylamino, methylthio, ethylthio,isopropylthio, ethylsulphinyl or ethylsulphonyl.

R⁵ is methoxymethyl, isopropyl, ethyl, butyl or 3,3-dimethylbutyl.

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl,isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl,3-butenyl, 1-propenyl or 3,3-dimethylbutyl.

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl,isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl,3-butenyl, 1-propenyl, 3,3-dimethylbutyl, phenethyl,dimethylaminomethyl, ethylaminomethyl, ethoxymethyl, methylthiomethyl,isopropylthiomethyl, ethylthiomethyl, ethylsulphinlmethyl,ethylsulphonylmethyl or isopropoxymethyl.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl orheterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy, ethoxy, trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl;

R⁵ is substituted methyl or optionally substituted C₂₋₆alkyl; whereinsaid substituents are selected from one or more methoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof;

provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl orheterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy, ethoxy, trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl;

R⁵ is substituted methyl, C₃₋₆cycloalkyl, optionally substitutedC₂₋₆alkenyl or optionally substituted C₂₋₆alkyl; wherein saidsubstituents are selected from one or more methoxy or hydroxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may beoptionally substituted on carbon by one or more hydroxy, methoxy, ethoxyor trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; or

R⁵ is substituted methyl, optionally substituted C₂ alkyl,C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein saidsubstituents are selected from one or more hydroxy, methoxy, ethoxy,isopropoxy, phenyl, ethylamino, dimethylamino, methylthio, ethylthio,isopropylthio, ethylsulphinyl or ethylsulphonyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine;or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl,3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl,cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, isopropyl or 1-methoxyprop-2-yl;

R⁵ is methoxymethyl, isopropyl, ethyl, butyl or 3,3-dimethylbutyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl,3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl,cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl;

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl,isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl,3-butenyl, 1-propenyl or 3,3-dimethylbutyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, 2-ethoxyethyl, 2-methoxyethyl, 2-hydroxyethyl,2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl,cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl; or

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl,isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl,3-butenyl, 1-propenyl, 3,3-dimethylbutyl, phenethyl,dimethylaminomethyl, ethylaminomethyl, ethoxymethyl, methylthiomethyl,isopropylthiomethyl, ethylthiomethyl, ethylsulphinlmethyl,ethylsulphonylmethyl or isopropoxymethyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine;or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

In another aspect of the invention, particular compounds of theinvention are any one of the Examples or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof.

In another aspect of the invention, particular compounds of theinvention are one of Examples 4, 12, 30, 31, 44, 51, 54, 58, 60 or 61 ora pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.

A particular aspect of the invention is that which relates to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof which process (wherein R¹, R², R³, R⁴,R⁵ and p are, unless otherwise specified, as defined in formula (I))comprises of:

Process a) reaction of a pyrimidine of formula (II):

wherein L is a displaceable group; with an aniline of formula (III):

Process b) reacting a compound of formula (IV):

with a compound of formula (V):

wherein T is O or S; R^(x) may be the same or different and isC₁₋₆alkyl;Process c) reacting a pyrimidine of formula (VI):

wherein X is a displaceable group; with an amine of formula (VII):R²—NH₂  (VII)orProcess d) reacting a pyrimidine of formula (VIII)

with a compound of formula (IX):

where Y is a displaceable group;and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt or in vivo    hydrolysable ester.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

X is a displaceable group, suitable values for X are for example, afluoro or chloro group. Preferably X is fluoro.

Y is a displaceable group, suitable values for Y are for example, ahalogeno or sulphonyloxy group, for example a bromo, iodo ortrifluoromethanesulphonyloxy group. Preferably Y is iodo.

Specific reaction conditions for the above reactions are as follows.

Process a) Pyrimidines of formula (II) and anilines of formula (III) maybe reacted together:

-   i) in the presence of a suitable solvent for example a ketone such    as acetone or an alcohol such as ethanol or butanol or an aromatic    hydrocarbon such as toluene or N-methyl pyrrolidine, optionally in    the presence of a suitable acid for example an inorganic acid such    as hydrochloric acid or sulphuric acid, or an organic acid such as    acetic acid or formic acid (or a suitable Lewis acid) and at a    temperature in the range of 0° C. to reflux, preferably reflux; or-   ii) under standard Buchwald conditions (for example see J. Am. Chem.    Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62,    1568 and 6066) for example in the presence of palladium acetate, in    a suitable solvent for example an aromatic solvent such as toluene,    benzene or xylene, with a suitable base for example an inorganic    base such as caesium carbonate or an organic base such as    potassium-t-butoxide, in the presence of a suitable ligand such as    2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and at a temperature in    the range of 25 to 80° C.

Pyrimidines of the formula (II) where L is chloro may be preparedaccording to Scheme 1:

Anilines of formula (III) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process b) Compounds of formula (IV) and compounds of formula (V) arereacted together in a suitable solvent such as N-methylpyrrolidinone orbutanol at a temperature in the range of 100-200° C., preferably in therange of 150-170° C. The reaction is preferably conducted in thepresence of a suitable base such as, for example, sodium hydride, sodiummethoxide or potassium carbonate.

Compounds of formula (V) may be prepared according to Scheme 2:

Compounds of formula (IV) and (Va) are commercially available compounds,or they are known in the literature, or they are prepared by standardprocesses known in the art.

Process c) Compounds of formula (VI) and amines of formula (VII) may bereacted together in the presence of an inert solvent such asN-methylpyrrolidinone or pyridine, in the presence of a base for examplean inorganic base such as caesium carbonate or in the presence of anorganic base such as excess (VII) and at a temperature in the range of25 to 80° C.

Compounds of formula (VI) (wherein X is chloro) may be preparedaccording to Scheme 3:

Compounds of formula (VIa) may be prepared according to Process a,Process b or Process d but wherein compounds (III), (IV) and (IX) arenot substituted by R²NHSO₂—.

Process d) Compounds of formula (VIII) and amines of formula (IX) may bereacted together under standard Buchwald conditions as described inProcess a.

The synthesis of compounds of formula (VIII) is described in Scheme 1.

Compounds of formula (IX) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Amines of formula (VI) are commercially available compounds, or they areknown in the literature, or they are prepared by standard processesknown in the art.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossesses anti-cell-proliferation activity such as anti-cancer activitywhich is believed to arise from the CDK inhibitory activity of thecompound. These properties may be assessed, for example, using theprocedures set out in WO 02/04429.

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) may be demonstrated at IC₅₀ concentrationsor doses in the range 250 μM to 1 nM in the in vitro assay described inWO 02/04429.

Typical IC₅₀ values for compounds of the invention when tested in theSRB assay described in WO 02/04429 are in the range 1 mM to 1 nM.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a pyrimidine derivative ofthe formula (I), or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof, as defined hereinbefore in association witha pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-50mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof, as defined hereinbefore for use in amethod of treatment of the human or animal body by therapy.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,are effective cell cycle inhibitors (anti-cell proliferation agents),which property is believed to arise from their CDK inhibitoryproperties. Accordingly the compounds of the present invention areexpected to be useful in the treatment of diseases or medical conditionsmediated alone or in part by CDK enzymes, i.e. the compounds may be usedto produce a CDK inhibitory effect in a warm-blooded animal in need ofsuch treatment. Thus the compounds of the present invention provide amethod for treating the proliferation of malignant cells characterisedby inhibition of CDK enzymes, i.e. the compounds may be used to producean anti-proliferative effect mediated alone or in part by the inhibitionof CDKs. Such a compound of the invention is expected to possess a widerange of anti-cancer properties as CDKs have been implicated in manycommon human cancers such as leukaemia and breast, lung, colon, rectal,stomach, prostate, bladder, pancreas and ovarian cancer. Thus it isexpected that a compound of the invention will possess anti-canceractivity against these cancers. It is in addition expected that acompound of the present invention will possess activity against a rangeof leukaemias, lymphoid malignancies and solid tumours such ascarcinomas and sarcomas in tissues such as the liver, kidney, prostateand pancreas. In particular such compounds of the invention are expectedto slow advantageously the growth of primary and recurrent solid tumoursof, for example, the colon, breast, prostate, lungs and skin. Moreparticularly such compounds of the invention, or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof, are expected toinhibit the growth of those primary and recurrent solid tumours whichare associated with CDKs, especially those tumours which aresignificantly dependent on CDKs for their growth and spread, includingfor example, certain tumours of the colon, breast, prostate, lung, vulvaand skin. Particularly “cancer” is selected from leukaemia, breastcancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer,bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidneycancer, skin cancer and cancer of the vulva.

It is further expected that a compound of the present invention willpossess activity against other cell-proliferation diseases in a widerange of other disease states including leukaemias, fibroproliferativeand differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore for use as amedicament; and the use of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined hereinbefore in the manufacture of a medicament for use inthe production of a cell cycle inhibitory (anti-cell-proliferation)effect in a warm-blooded animal such as man. Particularly, an inhibitoryeffect is produced by preventing entry into or progression through the Sphase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.

According to a further feature of the invention, there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined herein before in themanufacture of a medicament for use in the treatment of cancers (solidtumours and leukaemias), fibroproliferative and differentiativedisorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,arterial restenosis, autoimmune diseases, acute and chronicinflammation, bone diseases and ocular diseases with retinal vesselproliferation, particularly in the treatment of cancers.

According to a further feature of this aspect of the invention there isprovided a method for producing a cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound as defined immediately above.Particularly, an inhibitory effect is produced by preventing entry intoor progression through the S phase by inhibition of CDK2, CDK4 and/orCDK6, especially CDK2.

According to a further feature of this aspect of the invention there isprovided a method for producing a cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof as defined hereinbefore. Particularly, an inhibitory effect is produced by preventingentry into or progression through the S phase by inhibition of CDK2,CDK4 and/or CDK6, especially CDK2.

According to an additional feature of this aspect of the invention thereis provided a method of treating cancers (solid tumours and leukaemias),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation, in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof as defined herein before.

Particularly there is provided a method of treating cancer in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof as defined herein before.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the productionof a cell cycle inhibitory (anti-cell-proliferation) effect in awarm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the treatmentof cancers (solid tumours and leukaemias), fibroproliferative anddifferentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation, in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the treatmentof cancer in a warm-blooded animal such as man.

Preventing cells from entering DNA synthesis by inhibition of essentialS-phase initiating activities such as CDK2 initiation may also be usefulin protecting normal cells of the body from toxicity of cycle-specificpharmaceutical agents. Inhibition of CDK2 or 4 will prevent progressioninto the cell cycle in normal cells which could limit the toxicity ofcycle-specific pharmaceutical agents which act in S-phase, G2 ormitosis. Such protection may result in the prevention of hair lossnormally associated with these agents.

Therefore in a further aspect of the invention there is provided acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof for use as a cellprotective agent.

Therefore in a further aspect of the invention there is provided acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof for use inpreventing hair loss arising from the treatment of malignant conditionswith pharmaceutical agents.

Examples of pharmaceutical agents for treating malignant conditions thatare known to cause hair loss include alkylating agents such asifosfamide and cyclophosphamide; antimetabolites such as methotrexate,5-fluorouracil, gemcitabine and cytarabine; vinca alkaloids andanalogues such as vincristine, vinbalstine, vindesine, vinorelbine;taxanes such as paclitaxel and docetaxel; topoisomerase I inhibitorssuch as irintotecan and topotecan; cytotoxic antibiotics such asdoxorubicin, daunorubicin, mitoxantrone, actinomycin-D and mitomycin;and others such as etoposide and tretinoin.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,may be administered in association with a one or more of the abovepharmaceutical agents. In this instance the compound of formula (I) maybe administered by systemic or non systemic means. Particularly thecompound of formula (I) my may administered by non-systemic means, forexample topical administration.

Therefore in an additional feature of the invention, there is provided amethod of preventing hair loss during treatment for one or moremalignant conditions with pharmaceutical agents, in a warm-bloodedanimal, such as man, which comprises administering to said animal aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof.

In an additional feature of the invention, there is provided a method ofpreventing hair loss during treatment for one or more malignantconditions with pharmaceutical agents, in a warm-blooded animal, such asman, which comprises administering to said animal an effective amount ofa compound of formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof in simultaneous, sequential or separateadministration with an effective amount of said pharmaceutical agent.

According to a further aspect of the invention there is provided apharmaceutical composition for use in preventing hair loss arising fromthe treatment of malignant conditions with pharmaceutical agents whichcomprises a compound of formula (I), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, and said pharmaceuticalagent, in association with a pharmaceutically acceptable diluent orcarrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof, and apharmaceutical agent for treating malignant conditions that is known tocause hair loss.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt    or in vivo hydrolysable ester thereof, in a first unit dosage form;-   b) a pharmaceutical agent for treating malignant conditions that is    known to cause hair loss; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltor in vivo hydrolysable ester thereof, in the manufacture of amedicament for the prevention of hair loss during treatment of malignantconditions with pharmaceutical agents.

According to a further aspect of the present invention there is provideda combination treatment for the prevention of hair loss comprising theadministration of an effective amount of a compound of the formula (I),or a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof, optionally together with a pharmaceutically acceptable diluentor carrier, with the simultaneous, sequential or separate administrationof an effective amount of a pharmaceutical agent for treatment ofmalignant conditions to a warm-blooded animal, such as man.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

The CDK inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the cell cycle inhibitory treatment defined hereinbefore maybe: surgery, radiotherapy or chemotherapy. Such chemotherapy may coverthree main categories of therapeutic agent:

-   (i) other cell cycle inhibitory agents that work by the same or    different mechanisms from those defined hereinbefore;-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LHRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors); and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites (for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincristine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan). According to this aspect of the invention there is    provided a pharmaceutical product comprising a compound of the    formula (I) as defined hereinbefore and an additional anti-tumour    substance as defined hereinbefore for the conjoint treatment of    cancer.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated by the following non limitingexamples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations    were carried out at room or ambient temperature, that is, at a    temperature in the range of 18-25° C.;-   (ii) organic solutions were dried over anhydrous magnesium sulphate;    evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath    temperature of up to 60° C.;-   (iii) chromatography means flash chromatography on silica gel; thin    layer chromatography (TLC) was carried out on silica gel plates;-   (iv) in general, the course of reactions was followed by TLC and    reaction times are given for illustration only;-   (v) final products had satisfactory proton nuclear magnetic    resonance (NMR) spectra and/or mass spectral data;-   (vi) yields are given for illustration only and are not necessarily    those which can be obtained by diligent process development;    preparations were repeated if more material was required;-   (vii) when given, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    tetramethylsilane (TMS) as an internal standard, determined at 300    MHz using perdeuterio dimethyl sulphoxide (DMSO-d₆) as solvent    unless otherwise indicated; and peak multiplicities are shown as    follows: s, singlet; d, doublet; dd, double doublet; t, triplet; tt,    triple triplet; q, quartet; tq, triple quartet; m, multiplet; br,    broad;-   (viii) chemical symbols have their usual meanings; SI units and    symbols are used;-   (ix) solvent ratios are given in volume:volume (v/v) terms; and-   (x) mass spectra were run with an electron energy of 70 electron    volts in the chemical ionization (CI) mode using a direct exposure    probe; where indicated ionization was effected by electron impact    (EI), fast atom bombardment (FAB) or electrospray (ESP); values for    m/z are given; generally, only ions which indicate the parent mass    are reported; and unless otherwise stated, the mass ion quoted is    (MH)⁺;-   (xi) unless stated otherwise compounds containing an asymmetrically    substituted carbon and/or sulphur atom have not been resolved;-   (xii) where a synthesis is described as being analogous to that    described in a previous example the amounts used are the millimolar    ratio equivalents to those used in the previous example;-   (xvi) the following abbreviations have been used:

DMF dimethylformamide; EtOAc ethyl acetate; ether diethyl ether; MeOHmethanol; and DCM dichloromethane;

-   xvii) where an Isolute SCX-2 column is referred to, this means an    “ion exchange” extraction cartridge for adsorption of basic    compounds, i.e. a polypropylene tube containing a benzenesulphonic    acid based strong cation exchange sorbent, used according to the    manufacturers instructions obtained from International Sorbent    Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,    UK, CF82 7RJ;-   xviii) where an Isolute amine column is referred to, this means an    “ion exchange” extraction cartridge for adsorption of acidic    compounds, i.e. a polypropylene tube containing a amino silane    covalently bonded to a silica particle used according to the    manufacturers instructions obtained from International Sorbent    Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,    UK, CF82 7RJ; and-   xix) where a Chemelut column is referred to, this means an    extraction cartridge for removal of water, i.e. a polypropylene tube    containing diatomaceous earth used according to the manufacturers    instructions obtained from Varian, Harbor City, Calif., USA.

Example 14-(1-Methyl-2-isopropylimidazol-5-yl)-2-{4-[N-(cyclobutyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solutionof 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71;158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and themixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90minutes. The volatiles were removed by evaporation and the residue wasdried under high vacuum (<2 mmHg) for 1 hour. The resulting solid wasplaced under nitrogen and a solution of cyclobutylamine (100 μl, 1.08mmol) and diethylmethylamine (1 ml, 15 mmol) in MeOH (3 ml) added. Themixture was stirred for 30 minutes and the volatiles were evaporated invacuo. Trituration with water results in a solid which was washed water(3×20 ml) collected by filtration and dried under vacuum at 60° C. toyield the title compound (151 mg, 65%) as a solid. NMR: 1.24 (d, 6H),1.45 (m, 2H), 1.70 (m, 2H), 1.90 (m, 2H), 3.17 (m, 1H), 3.58 (m, 1H),3.98 (s, 3H), 7.19 (d, 1H), 7.70 (m, 4H), 7.92 (d, 2H), 8.41 (d, 1H),9.90 (brs, 1H); m/z 427.

Examples 2-23

The following compounds were prepared by the procedure of Example 1using the appropriate starting materials.

Ex R¹ R² R³ NMR M/z SM  2^(1,3) Et Et

1.25(t, 3H), 1.36(t, 3H), 1.51(m,1H), 1.78(m, 3H), 2.75(s, 2H),3.08(q,2H), 3.55(m, 1H), 3.65(m, 1H), 3.74(quin, 1H), 4.76(q,2H), 7.39(d, 1H),7.55(br t, 1H),7.72(d, 2H), 7.88(d, 2H), 8.49(s,1H), 8.65(d, 1H),10.16(s, 1H) 457 Meth73  3^(1,3) Et Et

1.25(t, 3H), 1.36(t, 3H), 2.87(s,2H), 3.08(q, 2H), 3.16(s, 3H),3.29(t,2H), 4.76(q, 2H), 7.40(d,1H), 7.55(brs, 1H), 7.73(d, 2H),7.88(d, 2H),8.51(s, 1H), 8.65(d,1H), 10.16(s, 1H) 431 Meth73  4^(1,3) Et Et

1.04(t, 3H), 1.25(t, 3H), 1.36(t,3H), 2.88(q, 2H), 3.09(q, 2H),3.34(m,4H), 4.76(q, 2H), 7.40(d,1H), 7.53(t, 1H), 7.72(d, 2H),7.88(d, 2H),8.49(s, 1H), 8.65(d,1H), 10.16(s, 1H) 445 Meth73  5^(1,3) Et Et

1.26(t, 3H), 1.37(t, 3H), 1.59(quintet, 2H), 2.76(m, 2H), 3.08(m, 2H),3.15(s, 3H), 3.27(t, 2H),4.76(q, 2H), 7.40(m, 2H), 7.71(d,2H), 7.89(d,2H), 8.49(s, 1H),8.67(d, 1H), 10.16(s, 1H) 445 Meth73  6^(1,4) EtMeOCH₂—

1.30(t, 3H), 1.55(m, 1H), 1.77(m,2H), 1.87(m, 1H), 2.79(m, 2H),3.45(s,3H), 3.60(m, 1H), 3.71(m,1H), 3.83(m, 1H), 4.77(q, 2H),4.87(s, 2H),7.42(d, 1H), 7.57(t,1H), 7.78(d, 2H), 7.90(d, 2H),8.45(s, 1H), 8.67(d,1H), 10.12(s,1H) 473 Meth72  7^(1,4) Et MeOCH₂—

1.05(t, 3H), 1.28(t, 3H), 2.88(m,2H), 3.35(q, 4H), 3.43(s, 3H),4.77(q,2H), 4.88(s, 2H), 7.40(d,1H), 7.52(brs, 1H), 7.73(d, 2H),7.88(d, 2H),8.53(s, 1H), 8.68(d,1H), 10.16(s, 1H) 461 Meth72  8^(1,4) Et MeOCH₂—

1.27(t, 3H), 1.59(quintet, 2H),2.78(q, 2H), 3.16(s, 3H), 3.28(t,2H),3.42(s, 3H), 4.75(q, 2H),4.84(s, 2H), 7.41(m, 2H), 7.73(d,2H), 7.89(d,2H), 8.44(s, 1H),8.67(d, 1H), 10.10(s, 1H) 461 Meth72  9^(1,4) EtMeOCH₂—

1.30(t, 3H), 2.88(q, 2H), 3.18(s,3H), 3.33(t, 2H), 3.45(s, 3H), 4.77(q,2H), 4.85(s, 2H), 7.40(d, 1H),7.55(t, 1H), 7.73(d, 2H), 7.90(d,2H),8.43(s, 1H), 8.67(d, 1H),10.12(s, 1H) 447 Meth72 10^(1,2) Me MeOCH₂—

0.07(m, 2H), 0.35(m, 2H), 0.80(m, 1H), 2.63(t, 2H), 3.30(s, 3H),4.02(s,3H), 4.55(s, 2H), 7.25(d,1H), 7.50(t, 1H), 7.70(m, 3H),7.90(d, 2H),8.48(d, 1H), 9.95(s,1H) 429 Meth70 11^(1,4) Me MeOCH₂—

1.52(m, 2H), 1.75(m, 2H), 1.91(m, 2H), 3.31(s, 3H), 3.61(m,1H), 4.03(s,3H), 4.55(s, 2H),7.28(d, 1H), 7.70(m, 4H), 7.90(d,2H), 8.51(d, 1H),9.98(s, 1H) 429 Meth70 12 i-Pr MeOCH₂—

1.06(t, 3H), 1.53(d, 6H), 2.84(m,2H), 3.16(m, 4H), 3.48(s, 3H),4.92(s,2H), 5.55(m, 1H), 7.27(d,1H), 7.53(m, 1H), 7.74(d, 2H),7.89(d, 2H),8.27(s, 1H), 8.71(d,1H), 10.19(s, 1H) 476 Meth69 13^(1,6) Me i-Pr

1.05(t, 3H), 1.40(d, 6H), 2.88(brq, 2H), 3.33(m, 4H), 3.55(br s),4.19(s,3H), 7.41(d, 1H), 7.57(brt, 1H), 7.76(d, 2H), 7.94(d, 2H),8.50(s, 1H),8.70(d, 1H), 10.29(s,1H) 445 Meth71 14^(1,7) Me i-Pr

1.41(d, 6H), 3.58(m, 1H), 3.68(m, 2H), 4.20(s, 3H)(not integratedascovered by overlappingexchangeables), 7.42(d, 1H), 7.80(d, 2H), 7.99(d,2H), 8.48(t, 1H),8.49(s, 1H), 8.70(d, 1H), 10.30(s,1H), 15.00(v br s,0.7H) 455 Meth71 15^(1,7) Me i-Pr

1.11(s, 9H), 1.41(d, 6H), 3.59(m,1H), 4.18(s, 3H), 7.35(s, 1H),7.41(d,1H), 7.78(d, 2H), 7.91(d,2H), 8.49(s, 1H), 8.70(d, 1H),10.22(s, 1H) 429Meth71 16 Me Et

1.08(s, 9H), 1.32(t, 3H), 3.05(q,2H), 4.08(s, 3H), 7.32(s, 1H),7.36(d,1H), 7.75(d, 2H), 7.89(d,2H), 8.41(s, 1H), 8.68(d, 1H),10.17(s, 1H) 415⁵ 17 Me c-Pr

1.08(t, 3H), 1.27(m, 4H), 2.40(m,1H), 2.89(m, 2H), 3.35(m, 4H),4.21(s,3H), 7.37(d, 1H), 7.50(m,1H), 7.73(d, 2H), 7.93(d, 2H),8.40(s, 1H),8.65(d, 1H), 10.24(s,1H) 443 Meth79 18 Me c-Pr

1.26(m, 4H), 2.40(m, 1H), 2.87(m, 2H), 3.18(s, 3H), 3.32(t, 2H),4.21(s,3H), 7.38(d, 1H), 7.53(m,1H), 7.73(d, 2H), 7.93(d, 2H),8.40(s, 1H),8.65(d, 1H), 10.24(s,1H) 429 Meth79 19 Me c-Pr

1.26(m, 4H), 1.65(m, 4H), 2.40(m, 1H), 2.78(m, 2H), 3.55(m,1H), 3.70(m,1H), 3.88(m, 1H),4.21(s, 3H), 7.38(d, 1H), 7.53(m,1H), 7.73(d, 2H),7.93(d, 2H),8.40(s, 1H), 8.67(d, 1H), 10.24(s,1H) 455 Meth79 20 Me c-Pr

0.30(m, 4H), 1.26(m, 4H), 1.65(m, 4H), 2.13(m, 1H), 2.40(m,1H), 4.21(s,3H), 7.38(d, 1H),7.73(m, 3H), 7.93(d, 2H), 8.40(s,1H), 8.67(d, 1H),10.22(s, 1H) 411 Meth79 21 n-Pr c-Pr

0.70(t, 2H), 1.05(t, 3H), 1.29(m,4H), 1.68(m, 2H), 2.50(m, 1H),2.85(m,2H), 3.33(m, 4H), 4.82(t,2H), 7.38(d, 1H), 7.53(m, 1H),7.73(d, 2H),7.87(d, 2H), 8.40(s,1H), 8.64(s, 1H), 10.17(s, 1H) 471 Meth80 22 n-Prc-Pr

0.70(t, 2H), 1.32(m, 4H), 1.68(m,2H), 2.50(m, 1H), 2.85(m, 2H),3.17(s,3H), 3.33(t, 2H), 4.82(t,2H), 7.38(d, 1H), 7.53(m, 1H),7.73(d, 2H),7.87(d, 2H), 8.41(s,1H), 8.64(s, 1H), 10.17(s, 1H) 457 Meth80 23 n-Prc-Pr

0.30(m, 4H), 0.70(t, 2H), 1.32(m,4H), 1.68(m, 2H), 2.05(m, 1H),2.50(m,1H), 3.17(s, 3H), 4.83(t,2H), 7.38(d, 1H), 7.74(m, 3H),7.87(d, 2H),8.41(s, 1H), 8.64(s,1H), 10.17(s, 1H) 439 Meth80 ¹Isolated as HCl salt²Purified by flash silica chromatography DCM:MeOH(Polarity increasingfrom 100:0 to 97:3) ³Purified by Isolute amine column ⁴Purified byIsolute amine column followed by flash silica chromatographyDCM:MeOH(Polarity increasing from 100:0 to 97:3) ⁵Example 29 of WO02/20512 ⁶Ethyldimethylamine used in place of diethylmethylamine.Work-up:- extracted with EtOAc, washed with dilute NaHCO₃, water andbrine ⁷Ethyldimethylamine used in place of diethylmethylamine. Productpurified by flash silica chromatography DCM:MeOH(96:4)

Example 244-(1-Methyl-2-isopropylimidazol-5-yl)-2-{4-[N-(cyclopropyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solutionof 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71;158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and themixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90minutes. The volatiles were removed by evaporation and the residue wasdried under high vacuum (<2 mmHg) for 1 hour. The resulting solid wasplaced under nitrogen and a solution of cyclopropylamine (570 μl, 8.1mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes andthe volatiles were evaporated in vacuo. Trituration with water resultsin a solid which was washed water (3×20 ml) collected by filtration anddried under vacuum at 60° C. to yield the title compound (205 mg, 92%)as a solid. NMR: 0.30 (m, 2H), 0.45 (m, 2H), 1.24 (d, 6H), 2.19 (m, 1H),3.17 (m, 1H), 4.01 (s, 3H), 7.19 (d, 1H), 7.70 (d, 2H), 7.92 (d, 2H),8.02 (m, 1H), 8.50 (d, 1H), 9.90 (brs, 1H); m/z 413.

Examples 25-71

The following compounds were prepared by the procedure of Example 24using the appropriate starting materials.

Ex R¹ R² R³ NMR M/z SM 25^(1,2) i-Pr MeOCH₂—

0.02(m, 2H), 0.38(m, 2H),0.75(m, 1H), 1.52(d, 6H),2.66(m, 2H), 3.43(s,3H),4.88(d, 2H), 5.52(m, 1H),7.28(d, 1H), 7.53(m, 1H),7.68(d, 2H),7.83(d, 2H), 8.23(s, 1H), 8.68(d, 1H), 10.16(brs, 1H) 457 Meth6926^(1,2) i-Pr MeOCH₂—

0.32(m, 2H), 0.53(m, 2H),1.52(d, 6H), 2.07(m, 1H),3.47(s, 3H), 4.92(d,2H), 5.52(m, 1H), 7.28(d, 1H), 7.74(m,3H), 7.83(d, 2H), 8.21(s,1H),8.68(d, 1H), 10.20(brs, 1H) 443 Meth69 27^(1,2) i-Pr MeOCH₂—

1.52(d, 6H), 2.86(q, 2H), 3.16(s, 3H), 3.28(t, 2H), 3.43(s,3H), 4.92(d,2H), 5.52(m,1H), 7.26(d, 1H), 7.56(m,1H), 7.72(d, 2H), 7.88(d,2H),8.23(s, 1H), 8.70(d, 1H),10.18(brs, 1H) 461 Meth69 28^(1,3) Et MeOCH₂—

0.38(m, 2H), 0.49(m, 2H),1.32(t, 3H), 2.15(brs, 1H),3.45(s, 3H), 4.80(q,2H), 4.88(s, 2H), 7.45(d, 1H), 7.78(d,3H), 7.95(d, 2H), 8.50(s,1H),8.70(d, 1H), 10.20(s, 1H) 429 Meth72 29^(1,4) Et MeOCH₂—

1.10(s, 9H), 1.27(t, 3H), 3.43(s, 3H), 4.78(q, 2H), 4.86(s,2H), 7.33(s,1H), 7.40(d, 1H),7.76(d, 2H), 7.86(d, 2H), 8.49(s, 1H), 8.69(d, 1H),10.11(s,1H) 445 Meth72 30^(1,3) Et Et

0.35(m, 2H), 0.48(m, 2H),1.25(t, 3H), 1.39(t, 3H), 2.09(s, 1H), 3.08(q,2H), 4.78(q,2H), 7.40(d, 1H), 7.75(d,3H), 7.92(d, 2H), 8.49(s,1H),8.67(d, 1H), 10.16(s, 1H) 413 Meth73 31^(1,3) Et Et

1.25(t, 3H), 1.36(t, 3H), 3.08(q, 2H), 3.40(m, 2H), 4.76(q,2H), 5.00(m,1H), 5.12(m,1H), 5.67(m, 1H), 7.40(d,1H), 7.64(br t, 1H), 7.73(d,2H),7.88(d, 2H), 8.49(s, 1H),8.65(d, 1H), 10.16(s, 1H) 413 Meth73 32^(1,4)Me MeOCH₂—

0.37(m, 2H), 0.48(m, 2H),2.12(brs, 1H), 3.30(s, 3H),4.03(s, 3H), 4.55(s,2H), 7.29(d, 1H), 7.68(m, 4H), 7.95(d,2H), 8.52(d, 1H), 10.00(s,1H) 415Meth70 33⁵ Me t-Bu—(CH₂)₂—

0.98(s, 9H), 1.60(m, 2H),2.78(m, 2H), 2.89(q, 2H),3.18(s, 3H), 3.30(m,2H),3.99(s, 3H), 7.20(d, 1H), 7.44(t, 1H), 7.63(s, 1H), 7.70(d,2H),7.93(d, 2H), 8.43(d,1H), 9.90(s, 1H) 473 Meth104 34⁵ Me t-Bu—(CH₂)₂—

0.98(s, 9H), 1.04(t, 3H), 1.60(m, 2H), 2.68(m, 2H), 2.87(m, 2H), 3.30(m,4H), 3.98(s,3H), 7.20(d, 1H), 7.42(t, 1H),7.64(s, 1H), 7.71(d, 2H),7.92(d, 2H), 8.43(d, 1H), 9.90(s,1H) 487 Meth104 35² Me n-Bu

0.90(3H, t), 1.04(3H, t), 1.38(2H, m), 1.66(2H, m), 2.74(2H, t),2.88(2H, q), 3.32(4H,m), 3.98(3H, s), 7.18(1H, d),7.42(1H, t), 7.71(2H,d), 7.92(2H, d), 8.44(1H, d), 9.90(1H, s) 459 Meth89 36² Me n-Bu

0.92(3H, t), 1.39(2H, m),1.68(2H, m), 2.74(2H, t),2.88(2H, q), 3.16(3H,s), 3.28(2H, hidden), 3.96(3H, s),7.19(1H, d), 7.46(1H, t), 7.64(1H, s),7.70(2H, d), 7.92(2H,d), 8.42(1H, d), 9.90(1H, s) 445 Meth89 37 i-Pri-Pr

1.44(d, 6H), 1.58(d, 6H), 2.86(m, 2H), 3.18(s, 3H), 3.27(t,2H), 3.70(m,1H), 5.60(m,1H), 7.26(d, 1H), 7.57(brs,1H), 7.73(d, 2H), 7.92(d,2H),8.28(s, 1H), 8.72(d, 1H),10.21(brs, 1H) 459 Meth76 38 Me Et

1.04(t, 3H), 1.36(t, 3H), 2.88(m, 2H), 3.04(q, 2H), 3.34(m,4H), 4.12(s,3H), 7.38(d, 1H),7.57(brs, 1H), 7.74(d, 2H),7.92(d, 2H), 8.42(s, 1H),8.68(d, 1H), 10.23(brs, 1H) 431 ⁷ 39 i-Pr i-Pr

1.03(t, 3H), 1.42(d, 6H), 1.57(d, 6H), 2.84(m, 2H), 3.34(m,4H), 3.69(m,1H), 5.59(m,1H), 7.25(d, 1H), 7.53(brs,1H), 7.72(d, 2H), 7.89(d,2H),8.26(s, 1H), 8.72(d, 1H),10.19(brs, 1H) 473 Meth76 40 Et i-Pr

1.33(t, 3H), 1.42(d, 6H), 3.09(m, 3H), 3.25(s, 3H), 3.42(t,2H), 4.63(q,2H), 4.86(t, 1H),7.04(d, 1H), 7.29(s, 1H), 7.59(s, 1H), 7.75(d, 2H),7.81(d,2H), 8.38(s, 1H) 446 Meth77 41 Et i-Pr

1.02(t, 3H), 1.13(t, 3H), 1.42(d, 6H), 2.83(m, 2H), 3.33(m,4H), 3.58(m,1H), 4.81(q,2H), 7.41(d, 1H), 7.59(brs,1H), 7.72(d, 2H), 7.91(d,2H),8.58(s, 1H), 8.63(d, 1H) 460 Meth77 42⁶ Et MeOCH₂—

1.30(t, 3H), 3.41(s, 3H), 3.66(quintet, 2H), 4.75(q, 2H),4.83(s, 2H),7.40(d, 1H), 7.77(d, 2H), 7.90(d, 2H), 8.35(m,2H), 8.66(d, 1H),10.07(s,1H) 471 Meth72 43⁶ Me MeOCH₂—

1.03(t, 3H), 2.90(m, 2H),3.32(q, 4H), 3.45(s, 3H), 4.13(s, 3H), 4.87(s,2H), 7.41(d,1H), 7.54(s, 1H), 7.75(d, 2H),7.93(d, 2H), 8.46(s, 1H),8.70(d, 1H), 10.26(s, 1H) 447 Meth70 44⁶ i-Pr c-Pr

1.30(m, 2H), 1.41(m, 2H),1.67(d, 6H), 2.58(m, 1H),2.92(q, 2H), 3.20(s,3H), 3.33(t, 2H), 5.75(quintet, 1H),7.31(d, 1H), 7.60(t, 1H), 7.79(d,2H), 7.91(d, 2H), 8.20(s,1H), 8.73(d, 1H), 10.23(s,1H) 457 Meth81 45⁶i-Pr c-Pr

1.09(t, 3H), 1.35(m, 2H),1.41(m, 2H), 1.67(d, 6H),2.57(m, 1H), 2.91(q,2H),3.38(m, 4H), 5.71(quintet,1H), 7.30(d, 1H), 7.58(t, 1H),7.76(d, 2H),7.90(d, 2H), 8.20(s, 1H), 8.72(d, 1H), 10.21(s,1H) 471 Meth81 46⁶ Etc-Pr

1.06(t, 3H), 1.30(m, 7H),2.48(m, 1H), 2.89(q, 2H),3.34(m, 4H), 4.88(q,2H),7.39(d, 1H), 7.53(t, 1H), 7.74(d, 2H), 7.90(d, 2H), 8.40(s,1H),8.66(d, 1H), 10.12(s,1H) 457 Meth82 47⁶ Et c-Pr

1.25(m, 4H), 1.35(t, 3H),2.45(m, 1H), 2.89(q, 2H),3.17(s, 3H), 3.30(t,2H), 4.88(q, 2H), 7.40(d, 1H), 7.55(t,1H), 7.75(d, 2H), 7.90(d,2H),8.41(s, 1H), 8.67(d, 1H),10.12(s, 1H) 443 Meth82 48 n-Pr MeOCH₂—

(400 MHz) 0.71(t, 3H), 1.60(sext, 2H), 2.89(q, 2H), 3.19(s, 3H), 3.32(q,2H), 3.43(s,3H), 4.67(t, 2H), 4.83(s, 2H),7.37(d, 1H), 7.53(t, 1H),7.72(d, 2H), 7.87(d, 2H), 8.35(s,1H), 8.64(d, 1H), 10.10(s,1H) 461Meth75 49 n-Pr MeOCH₂—

(400 MHz) 0.69(t, 3H), 1.07(t,3H), 1.61(sext, 2H), 2.89(q,2H), 3.34(m,4H), 3.42(s,3H), 4.68(t, 2H), 4.81(s, 2H),7.37(t, 1H), 7.52(t, 1H),7.73(d, 2H), 7.88(d, 2H), 8.36(s,1H), 8.68(s, 1H), 10.13(s,1H) 475Meth75 50⁸ Me n-Pr

0.97(t, 3H), 1.70(m, 2H),2.70(t, 2H), 2.89(q, 2H), 3.17(s, 3H), 3.28(t,2H), 3.95(s,3H), 7.20(d, 1H), 7.44(t, 1H),7.64(s, 1H), 7.70(d, 2H),7.92(d, 2H), 8.42(d, 1H), 9.89(s,1H) 431 Meth91 51⁸ Me n-Pr

0.98(t, 3H), 1.04(t, 3H), 1.70(m, 2H), 2.70(t, 2H), 2.86(q,2H), 3.31(m,4H), 3.97(s,3H), 7.19(d, 1H), 7.44(t, 1H),7.64(s, 1H), 7.70(d, 2H),7.92(d, 1H), 8.42(d, 1H), 9.90(s,1H) 445 Meth91 52⁹ Me MeO(CH₂)₂—

3.05(t, 2H), 3.15(q, 2H), 3.29(s, 3H), 3.38(s, 3H), 3.44(t,2H), 3.84(t,2H), 4.0(s, 3H),4.92(t, 1H), 7.02(d, 1H), 7.41(br s, 1H), 7.59(s, 1H),7.80(m, 4H), 8.40(d, 1H) 447 Meth92 53⁹ Me MeO(CH₂)₂—

1.15(t, 3H), 3.05(t, 2H), 3.14(q, 2H), 3.38(s, 3H), 3.44(m,4H), 3.84(t,2H), 3.98(s, 3H),5.01(t, 1H), 7.04(d, 1H), 7.50(br s, 1H), 7.80(m, 4H),8.40(d, 1H) 461 Meth92 54 Et n-Pr

0.98(t, 3H), 1.19(t, 3H), 1.75(q, 2H), 2.69(t, 2H), 2.88(q,2H), 3.30(t,2H), 4.59(m,2H), 7.22(d, 1H), 7.46(t, 1H),7.74(m, 3H), 7.88(d,2H),8.42(d, 1H), 9.83(s, 1H) 445 Meth93 55 Et n-Pr

0.98(t, 3H), 1.06(t, 3H), 1.19(t, 3H), 1.74(m, 2H), 2.70(t,2H), 2.88(q,2H), 3.36(m,4H), 4.59(m, 2H), 7.22(d,1H), 7.44(t, 1H), 7.70(m,3H),7.88(d, 2H), 8.42(d,1H), 9.82(s, 1H) 458 Meth93 56 Et n-Bu

0.97(t, 3H), 1.18(t, 3H), 1.40(m, 2H), 1.70(m, 2H), 2.72(t,2H), 2.88(q,2H), 3.17(s, 3H),3.27(t, 2H), 4.59(q, 2H), 7.21(d, 1H), 7.44(t, 1H),7.70(s,1H), 7.72(d, 2H), 8.42(d,1H), 9.81(s, 1H) 458 Meth94 57 Et n-Bu

0.92(t, 3H), 1.06(t, 3H), 1.18(t, 3H), 1.38(m, 2H), 1.69(m,2H), 2.74(t,2H), 2.88(q, 2H),3.37(m, 2H), 4.58(q, 2H),7.20(d, 1H), 7.43(t, 1H),7.68(s, 1H), 7.70(d, 2H), 7.84(d,2H), 8.42(d, 1H), 9.82(s, 1H) 473Meth94 58⁸ i-Pr n-Pr

1.0(t, 1H), 1.48(d, 6H), 1.79(m, 2H), 2.78(t, 2H), 2.86(m,2H), 3.30(t,2H), 5.59(m,1H), 7.15(d, 1H), 7.45(m,2H), 7.78(d, 2H), 7.88(d,2H),8.44(d, 1H), 9.86(s, 1H) 459 Meth95 59⁸ i-Pr n-Pr

1.0(m, 6H), 1.48(d, 6H), 1.78(m, 2H), 2.77(t, 2H), 2.85(q,2H), 3.32(m,4H), 5.58(m,1H), 7.16(d, 1H), 7.44(m,2H), 7.69(d, 2H), 7.88(d,2H),8.45(d, 1H), 9.85(s, 1H) 473 Meth95 60⁸ i-Pr Et

1.28(t, 3H), 2.48(d, 6H), 2.86(m, 4H), 3.29(t, 2H), 5.59(m,1H), 7.15(d,1H), 7.44(m,2H), 7.70(d, 2H), 7.86(d,2H), 8.45(d, 1H), 9.84(s, 1H) 445Meth96 61⁸ i-Pr Et

1.04(t, 3H), 1.28(t, 3H), 1.46(d, 6H), 2.82(m, 4H), 3.35(m,4H), 5.59(m,1H), 7.15(d,1H), 7.24(m, 2H), 7.69(d,2H), 7.86(d, 2H), 8.43(d,1H),9.85(s, 1H) 459 Meth96 62 i-Pr EtOCH₂—

1.20(t, 3H), 1.52(d, 6H), 2.86(m, 2H), 3.15(s, 3H), 3.29(t,2H), 3.63(m,2H), 4.92(s,2H), 5.52(m, 1H), 7.27(d,1H), 7.53(t, 1H), 7.71(d,2H),7.87(d, 2H), 8.22(s, 1H), 8.70(d, 1H), 10.16(s, 1H) 475 Meth78 63 Mei-PrCH₂—

0.96(d, 6H), 2.15–2.08(m,1H), 2.61(d, 2H), 2.88(q,2H), 3.18(s, 3H),3.30–3.25(m, 2H), 3.98(s, 3H), 7.20(d,1H), 7.44(t, 1H), 7.64(s,1H),7.72(d, 2H), 7.92(d, 2H), 8.42(d, 1H), 9.90(s, 1H) 445 Meth109 64 Mei-PrCH₂—

0.95(d, 6H), 1.03(t, 3H),2.15–2.07(m, 1H), 2.30(d,2H), 2.88(q, 2H),3.18(d,2H), 3.38–3.30(m, 2H), 3.98(s, 3H), 7.20(d, 1H), 7.43(t,1H),7.73–7.64(m, 3H), 7.90(d, 2H), 8.42(d, 1H), 9.90(s,1H) 459 Meth109 65n-Pr n-Pr

0.62(t, 3H), 1.0(t, 3H), 1.51(q, 2H), 1.75(q, 2H), 2.70(t,2H), 2.89(q,2H), 3.18(s, 3H),3.30–3.25(m, 2H), 4.52(t,2H), 7.20(d, 1H), 7.48(t,1H),7.74–7.65(m, 3H), 7.88(d,2H), 8.42(d, 1H), 9.82(s, 1H) 459 Meth99 66n-Pr n-Pr

0.68(t, 3H), 0.99(t, 3H), 1.04(t, 3H), 1.50(q, 2H), 1.6(q,2H), 2.70(t,2H), 2.92–2.85(m, 2H), 3.39–3.28(m, 2H),4.51(t, 2H), 7.20(d, 2H),7.43(t, 1H), 7.68(s, 1H), 7.70(d,2H), 7.88(d, 2H), 8.42(d,1H), 9.82(s,1H) 473 Meth99 67 n-Pr t-Bu(CH₂)₂—

0.70(t, 3H), 0.98(s, 9H), 1.46–1.64(m, 4H), 2.62–2.72(m,2H), 2.87(q,2H), 3.18(s, 3H),3.27–3.30(m, 2H), 4.53(t,2H), 7.20(d, 1H), 7.48(t,1H),7.63(s, 1H), 7.71(d, 2H), 7.87(d, 2H), 8.42(s, 1H), 9.82(s,1H) 501Meth115 68 Et n-Pr

0.96(t, 3H), 1.17(t, 3H), 1.73(m, 2H), 2.69(t, 2H), 2.77(q,2H), 3.35(q,2H), 4.59(m,3H), 7.21(d, 1H), 7.34(t, 1H),7.69(m, 3H), 7.89(d,2H),8.41(d, 1H), 9.81(s, 1H) 431 Meth93 69 Et n-Pr NH₂ 0.98(t, 3H),1.25(t, 3H), 1.80(m, 2H), 3.06(t, 2H), 4.78(q,2H), 7.09(br s, 4H),7.39(d,1H), 7.75(d, 2H), 7.86(d,2H), 8.51(s, 1H), 8.64(d, 1H),10.14(s,1H) 387 Meth93 70¹⁰ n-Pr Me₂NCH₂—

0.68(t, 3H), 1.54(q, 2H), 2.18(s, 6H), 2.89(q, 2H), 3.17(s,3H), 3.30(m,2H), 3.53(s,2H), 4.59(t, 2H), 7.22(d, 1H),7.43(t, 1H), 7.66(s, 1H),7.77(d, 2H), 7.84(d, 2H), 8.44(d,1H), 9.84(s, 1H) 474 Meth119 71¹⁰ n-PrEtNHCH₂—

0.68(t, 3H), 1.05(t, 3H), 1.51(m, 2H), 2.57(m, 2H), 2.88(m, 2H), 3.18(s,3H), 3.28(m,2H), 3.80(s, 2H), 4.59(t, 2H),7.20(d, 1H), 7.50(s, 1H),7.68(s, 1H) 7.70(d, 2H), 7.88(d,2H), 8.43(d, 1H), 9.85(s, 1H) 474Meth120 ¹Isolated as HCl salt ²Purified by flash silica chromatographyDCM:MeOH(Polarity increasing from 100:0 to 97:3) ³Purified by Isoluteamine column ⁴Purified by Isolute amine column followed by flash silicachromatography DCM:MeOH(Polarity increasing from 100:0 to 97:3)⁵Purified by flash silica chromatography DCM:MeOH(95:5) ⁶Purified byIsolute amine column followed by flash silica chromatographyDCM:MeOH(Polarity increasing from 100:0 to 97:3) and isolated as the HClsalt ⁷Example 29 of WO 02/20512 ⁸Purified by flash silica chromatographyDCM:MeOH(98:2) ⁹Purified by flash silica chromatographyDCM:MeOH(98.5:1.5) ¹⁰Purified by chromatography on silica gel elutingwith DCM:MeOH(90:10)

Example 724-[1-(Methoxypropyl-2-yl)-2-(methoxymethyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

To a stirred solution of2-amino-4-(1-methoxyisopropyl-2-methoxymethylimidazol-5-yl)pyrimidine(Method 85; 163 mg, 0.6 mmol),N-(2-ethoxyethyl)-4-iodobenzenesulphonamide (Method 1; 400 mg, 1.2mmol), tris(dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol)and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg, 0.076 mmol) indioxane (10 ml) was added sodium t-butoxide (258 mg, 2.69 mmol) and themixture heated at 80° C. overnight. The reaction was cooled to roomtemperature and MeOH (5 ml) was added and the mixture poured onto anIsolute SCX-2 column, eluted first with MeOH (10×30 ml) and the productwas then eluted with 5% methanolic ammonia (10×30 ml). The solvent wasremoved by evaporation and the residue purified by flash chromatographyon silica gel eluting with DCM/MeOH (100:0 increasing in polarity to97:3) to yield a foam which was dissolved in MeOH (2 ml) and treatedwith 1N HCl in ether (350 μl, 0.35 mmol) for 5 minutes. Solvent wasevaporated in vacuo to yield a yellow foam which was triturated withether to yield after filtration the title compound as a yellow solid (63mg, 20%) NMR: 1.02 (t, 3H), 1.54 (d, 3H), 2.87 (m, 2H), 3.14 (s, 3H),3.30 (m, 4H), 3.43 (s, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 4.90 (s, 2H),5.65 (m, 1H), 7.26 (d, 1H), 7.54 (m, 1H), 7.71 (d, 2H), 7.88 (d, 2H),8.26 (s, 1H), 8.70 (d, 1H), 10.20 (brs, 1H); m/z 505.

Examples 73-74

The following compounds were prepared by the procedure of Example 72using the appropriate starting materials.

Ex R¹ NMR M/z SM 73

1.37(t, 3H), 3.06(q,2H), 3.62(m, 2H), 4.12(s, 3H), 7.39(d, 1H),7.77(d,1H), 7.94(d,1H), 8.42(s, 1H), 8.44(t, 1H), 8.65(d, 1H),10.28(brs, 1H)441 Meth86Meth2 74

1.35(t, 3H), 1.58(m,2H), 2.76(m, 2H), 3.04(q, 2H), 3.17(s, 3H),3.24(t,2H), 4.10(s,3H), 7.37(d, 1H), 7.39(t, 1H), 7.71(d, 1H),7.92(d, 1H),8.39(s,1H), 8.66(d, 1H), 10.21(brs, 1H) 431 Meth86Meth3

Example 752-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-[1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl]pyrimidine

The title compound was prepared by the procedure of Method 89 usingExample 35 of WO 02/20512 and acetone as the starting materials. NMR:1.20 (s, 6H), 2.88-2.83 (m, 4H), 3.18-3.15 (m, 5H), 4.0 (s, 3H), 4.78(s, 1H), 7.20 (d, 1H), 7.44 (t, 1H), 7.70-7.67 (m, 3H), 7.90 (d, 2H),8.46 (d, 1H), 9.90 (s, 1H); m/z 461.

Example 764-[2-(Prop-1-enyl)-1-(isopropyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

n-Butyl lithium (656 μl of a 1.6 N solution in hexane, 1.05 mmol), wasadded dropwise to a solution of ethyl triphenylphosphonium iodide (437mg, 1.05 mmol), in anhydrous THF (15 ml), under nitrogen at 0° C. Asolution of4-(2-formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine(Method 105; 300 mg, 0.523 mmol), in THF (5 ml), was then slowly added.The mixture was allowed to warm to ambient temperature and stirred for18 hours. The volatiles were removed by evaporation and the residuedissolved in EtOAc (40 ml), washed with water (2×15 ml), brine (15 ml),and dried. The solvent removed by evaporation to give a crude product(254 mg), as a yellow foam. The crude product was purified bychromatography on silica-gel eluting with 3% MeOH in DCM), the semi-pureproduct (70 mg), was dissolved in TFA/H₂O (1:1, 10 ml), and stirred for1 hour. The TFA was removed by evaporation, the resulting aqueoussolution neutralised with saturated NaHCO₃, and the product extractedwith DCM (3×5 ml). The extracts were combined, dried and the solventremoved. The residue was purified by preparative reverse phase HPLC,eluting with acetonitrile/H₂O, 0.01% formic buffer. Pure fractions wereneutralised with 2N aqueous sodium hydroxide solution. The resultingwhite precipitate, was collected by filtration and dried to give thetitle compound (1:2.5 mixture of E:Z isomers), as a white solid (5 mg,2%). NMR: Z isomer 1.51 (d, 6H), 2.09 (d, 3H), 2.92 (t, 2H), 3.17 (s,3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.05 (m, 1H), 6.51 (m, 1H), 7.1 (br s,1H), 7.16 (d, 1H), 7.57 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.48 (d,1H), 9.47 (s, 1H); E isomer 1.51 (d, 6H), 1.94 (d, 3H), 2.92 (t, 2H),3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.60 (m, 1H), 6.67 (m, 1H),7.1 (br s, 1H), 7.13 (d, 1H), 7.47 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H),8.44 (d, 1H), 9.47 (s, 1H); m/z: 457.

Example 774-[2-(2-Methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

Aqueous TFA (90%) was added to a mixture of4-[2-(2-methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)-N-t-butylsulphamoyl]anilino}pyrimidine(Method 111; 70 mg, 0.14 mmol), and anisole (90 μl, 0.83 mmol), and themixture stirred at ambient temperature for 1 hour. The volatiles wereevaporated and the residue dissolved in water. The solution wasneutralised (NaHCO₃), and extracted with EtOAc. The extracts were dried,and the solvent evaporated to give the title compound (30 mg, 41%). NMR:1.19 (t, 3H), 1.99 (s, 3H), 2.15 (s, 3H), 2.89 (q, 2H), 3.18 (s, 3H),3.30-3.28 (m, 2H), 4.65 (q, 2H), 6.28 (s, 1H), 7.25 (d, 1H), 7.50 (t,1H), 7.70 (d, 2H), 7.85 (s, 1H), 7.89 (d, 2H), 8.45 (d, 1H), 9.85 (s,1H); m/z: 457.

Example 784-[2-(2-Methylprop-1-enyl)-1-methylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}4-[t-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl]pyrimidine(Example 75), was treated by the procedure described in Method 110 togive the title compound (30 mg, 14%). NMR: 1.99 (s, 3H), 2.15 (s, 3H),2.87 (q, 2H), 3.18 (s, 3H), 3.23-3.30 (m, 2H), 4.0 (s, 3H), 6.26 (s,1H), 7.22 (d, 1H), 7.43 (t, 1H), 7.70 (d, 2H), 7.79 (s, 1H), 7.92 (d,2H), 8.44 (d, 1H), 9.90 (s, 1H); m/z: 443.

Example 794-[2-(But-3-en-1-yl)-1-propylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

A mixture of caesium fluoride (180 mg, 1.2 mmole), and4-(2-(but-3-enyl)-1-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine(Method 100; 100 mg, 0.17 mmol), in DMF (3 ml), was heated at 140° C.under nitrogen for 24 hours. The mixture was diluted with water andextracted with EtOAc. The extracts were washed with water and brine,dried, and the solvent evaporated. The residue was purified bychromatography on silica gel eluting with EtOAc to give the titlecompound. (8 mg, 10%). NMR: 0.7 (t, 3H), 1.52 (q, 2H), 2.80 (t, 2H),2.85-2.89 (m, 2H), 3.19 (s, 3H), 3.18-3.22 (m, 2H), 3.30 (t, 2H), 4.52(t, 2H), 4.98 (d, 1H), 5.10 (dd, 1H), 5.95-5.89 (m, 1H), 7.20 (d, 1H),7.44 (t, 1H), 7.70 (s, 3H), 7.74 (d, 2H), 7.89 (d, 2H), 8.45 (d, 1H),9.80 (s, 1H); m/z: 471.

Example 804-[2-(Methylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Sodium thiomethoxide (21 mg, 0.3 mmol) was added to a stirred solutionof4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine(Method 116; 52 mg, 0.1 mmol) in MeOH (5 ml) and the solution wasstirred at ambient temperature for 3 hour. The solvent was removedevaporation and the residue was partitioned between water and EtOAc. Theorganic phase was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried (Na₂SO₄) and the volatiles removedby evaporation. The residue was triturated with ether and collected byfiltration. This solid was suspended in MeOH (2 ml) and 1.0M etherealhydrogen chloride was added to give a clear solution. The volatiles wereremoved by evaporation and the residue triturated with ether giving thetitle compound (42 mg, 80%) as the hydrochloride salt. NMR: 0.72 (t,3H), 1.06 (t, 3H), 1.63 (m, 2H), 2.18 (s, 3H), 2.88 (q, 2H), 3.35 (m,4H), 4.42 (s, 2H), 4.72 (m, 2H), 7.37 (d, 1H), 7.54 (t, 1H), 7.75 (d,2H), 7.89 (d, 2H), 8.39 (s, 1H), 8.68 (d, 1H), 10.14 (s, 1H); m/z 491.

Examples 81-82

The following compounds were prepared by the procedure of Example 80using4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine(Method 116) and the appropriate reagent but without conversion of thefree base product to hydrochloride salt.

M/z Ex Compound NMR [MH]+ 81 4-[2-(Isopropylthiomethyl)-1- 0.67(t, 3H),1.03(t, 3H), 1.20(d, 6H), 519 (propyl)imidazol-5-yl]-2-{4- 1.55(m, 2H),2.85(m, 2H), 2.93(m, 1H), [N-(2-ethoxyethyl)sulphamoyl] 3.33(m, 4H),3.94(s, 2H), 4.55(t, 2H), anilino}pyrimidine 7.21(d, 1H), 7.45(t, 1H),7.68(s, 1H), 7.72(d, 2H), 7.84(d, 2H), 8.45(d, 1H), 9.85(s, 1H) 824-[2-(Ethylthiomethyl)-1- 0.68(t, 3H), 1.04(t, 3H), 1.17(t, 3H), 505(propyl)imidazol-5-yl]-2-{4- 1.55(m, 2H), 2.53(m, 2H), 2.86(q, 2H),[N-(2-ethoxyethyl)sulphamoyl] 3.33(m, 4H), 3.90(s, 2H), 4.55(t, 2H),7.21(d, anilino}pyrimidine 1H), 7.45(t, 1H), 7.68(s, 1H), 7.72(d, 2H),7.84(d, 2H), 8.45(d, 1H), 9.85(s, 1H)

Example 834-[2-(Ethylsulphinylmethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) wasadded to a stirred solution of4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine(Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution wasstirred for 18 hours. The MeOH was removed by evaporation and theaqueous residue was extracted with EtOAc. The extracts were combined,washed with brine, dried and the volatiles removed by evaporation. Theresidue was purified by chromatography on silica gel eluting withDCM/MeOH (95:5 increasing in polarity to 90:10) and the purified producttriturated with ether to give the title compound (37 mg, 51%). NMR: 0.68(t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33(m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H),7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H);m/z 521.

Example 844-[2-(Ethylsulphonylmethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Oxone (123 mg, 0.2 mmol) was added to a stirred solution of4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine(Example 82; 70 mg, 0.14 mmol) in MeOH/acetone/water (15:5:3) (2 ml) at0-4° C. The solution was allowed to warm to ambient temperature andstirred for 2 hr. The reaction mixture was diluted with water andextracted with EtOAc. The extracts were combined, washed with brine,dried (Na₂SO₄) and the volatiles removed by evaporation. The residue waspurified by chromatography on silica gel eluting with DCM/MeOH (95:5)and the purified product triturated with ether to give the titlecompound (44 mg, 59%). NMR: 0.65 (t, 3H), 1.03 (t, 3H), 1.27 (t, 3H),1.52 (m, 2H), 2.85 (q, 2H), 3.30 (m, 6H), 4.64 (t, 2H), 4 81 (s, 2H),7.25 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.79 (s, 1H), 7.97 (d, 2H),8.50 (d, 1H), 9.91 (s, 1H); m/z 537.

Example 854-[2-(Isopropoxymethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Sodium isopropoxide (87 mg, 1.05 mmol) was added to a stirred suspensionof4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine(Method 116; 100 mg, 0.21 mmol) in isopropanol (20 ml). The reaction wasstirred for 48 hours at ambient temperature, and was then poured intowater (80 ml) and extracted with EtOAc (3×30 ml). The extracts werecombined washed with brine (2×40 ml), dried and the volatiles removed byevaporation. The residue was purified by reverse phase HLPC (C18 column)eluting with aqueous ammonia/water/acetonitrile (5:90:5 decreasing inpolarity to (5:0:95) to give the title compound (18 mg, 17%) as a browngum. M/z 503.

Example 864-[2-(Phenethyl)-1-(methyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine(Method 117; 115 mg, 0.219 mmol) and triethylamine (34 μl, 0.241 mmol)was dissolved in ethanol (20 ml) and EtOAc (10 ml) and 30% palladium oncharcoal catalyst (30 mg) added. The mixture was stirred for 3 daysunder an atmosphere of hydrogen. The catalyst was removed by filtrationand filtrate evaporated. The residue was dissolved in DCM (20 ml),washed with water (2×5 ml), dried and the solvent removed by evaporationto give the title compound (67 mg, 63%) as a white solid. NMR: 2.88 (q,2H) 3.05 (s, 4H) 3.16 (s, 3H) 3.28 (t, 3H) 3.90 (s, 3H) 7.21 (d, 1H)7.28 (m, 5H) 7.69 (s, 1H) 7.70 (d, 2H) 8.44 (d, 1H) 9.94 (s, 1H); m/z493.

Preparation of Starting Materials

The starting materials for the examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1

N-(2-Ethoxyethyl)-4-iodobenzenesulphonamide

2-Ethoxyethylamine (2.14 g, 24 mmol) and diisopropylethylamine (4.2 ml,24 mmol) were dissolved in DCM (50 ml) and cooled to 0° C. To this wasadded pipsyl chloride (6.05 g, 20 mmol) in portions and the reactionstirred for 18 hours. Volatiles were evaporated in vacuo. The residuewas dissolved in EtOAc (50 ml), extracted 1N citric acid (2×50 ml),brine (50 ml), dried and evaporated in vacuo to yield an oil whichsolidified on standing to give the title compound as a pale yellow solid(6.97 g, 98%). NMR: 1.01 (t, 3H), 2.89 (q, 2H), 3.30 (m, 4H), 7.53 (d,2H), 7.75 (t, 1H), 7.97 (d, 2H); m/z 354 (M−H)⁻.

Methods 2-5

The following compounds were prepared by the procedure of Method 1 usingthe appropriate starting materials.

Meth Compound NMR M/z 2 N-(2,2,2-trifluoroethyl)-4- 3.69(q, 2H), 7.58(d,2H), 7.93(d, 2H), 364(M−H)⁻ iodosulphonamide 8.65(brs, 1H) 3N-(3-Methoxypropyl)-4- 1.68(m, 2H), 3.02(q, 2H), 3.21(s, 3H), 3.38(t,356 iodobenzenesulphonamide 2H), 5.10(s, 1H), 7.51(d, 2H), 7.80(d, 2H) 4N-(2-Methoxyethyl)-4- 3.14(q, 2H), 3.25(s, 3H), 3.40(q, 2H), 4.97(s, 342iodobenzenesulphonamide 1H), 7.58(d, 2H), 7.90(d, 2H) 5 N-t-Butyl-4-1.08(s, 9H), 7.56(m, 3H), 7.94(d, 2H) 338[MH]⁻ iodobenzenesulphonamide

Methods 6-7

The following compounds were synthesised by the procedure as describedin JOC 1987, 2714-2716.

Meth Compound 6 5-Methyl-4-(methylamino)isoxazole hydrochloride 75-Acetyl-1-methyl-2-(methoxymethyl)imidazole

Methods 8-49

The following compounds were prepared using procedures analogous tothose described in JOC 1987, 2714-2726.

Meth Compound NMR M/z SM 8 5-Methyl-4-(N- 1.09(t, 3H), 2.08(q, 2H), 169Meth 6 methyl-N- 2.38(s, 3H), 3.16(s, 3H), propionylamino) 8.16(s, 1H)isoxazole 9 1-Methyl-2-ethyl-5- 1.36(t, 3H), 2.41(s, 3H), 153 Meth 8acetylimidazole 2.72(q, 2H), 3.82(s, 3H), 7.72(s, 1H) 104-(Isopropylamino)-5- (CDCl₃) 1.12(d, 6H), 141 4-Amino-5-methylisoxazole 2.30(s, 3H), 3.21(1H, sept), methylisoxazole 8.01(s, 1H)hydrochloride 11 5-Methyl-4-(N- 0.95(d, 6H), 2.35(s, 3H), 213 Meth 10isopropyl-N- 3.20(s, 3H), 3.60(s, 2H), methoxyacetamido) 4.70(m, 1H),8.60(s, 1H) isoxazole 12 1-isopropyl-2- 1.43(d, 6H), 2.40(s, 3H), 197Meth 11 methoxymethyl-5- 3.24(s, 3H), 4.50(s, 2H), acetylimidazole4.90(m, 1H), 7.92(s, 1H) 13 5-Methyl-4-(N- 1.03(d, 6H), 2.36(s, 3H), 183Meth 6 methyl-N- 2.48(m, 1H), 3.16(s, 3H), isobutyrylamino) 8.20(s, 1H)isoxazole 14 1-Methyl-2-isopropyl- 1.36(d, 6H), 2.42(s, 3H), 167 Meth 135-acetylimidazole 3.10(m, 1H), 3.84(s, 3H), 7.75(s, 1H) 155-Methyl-4-(N- 2.00(s, 3H), 2.34(s, 3H), 141 4-Amino-5-acetamido)isoxazole 8.64(s, 1H), 9.60(brs, 1H) methylisoxazolehydrochloride 16 5-Methyl-4- 1.21(t, 3H), 2.58(s, 3H), 127 Meth 15(ethylamino)isoxazole 3.22(q, 2H), 8.76(s, 1H) hydrochloride 175-Methyl-4-(N-ethyl- (CDCl₃) 1.12(t, 3H), 2.39(s, 199 Meth 16N-methoxyacetamido) 3H), 3.36(s, 3H), 3.64(q, isoxazole 2H), 3.75(s,2H), 8.16(s, 1H) 18 5-Acetyl-1-ethyl-2- (CDCl₃) 1.37(t, 3H), 2.48(s, 183Meth 17 methoxymethyl 3H), 3.38(s, 3H), 4.39(q, imidazole 2H), 4.56(s,2H), 7.74(s, 1H) 19 5-Methyl-4-(N-ethyl- (CDCl₃) 1.11(q, 6H), 1835-Methyl-4- N-propylamido) 2.05(q, 2H), 2.39(s, 3H), 3.65(q,(ethylamino)isoxazole isoxazole 2H) 8.16(s, 1H) hydrochloride 205-Acetyl-1,2- (CDCl₃) 1.35(m, 6H), 167 Meth 19 diethylimidazole 2.45(s,3H), 2.73(q, 2H), 4.30(q, 2H), 7.73(s, 1H) 21 5-Methyl-4- 1.01(d, 3H),2.06(s, 3H), 171 4-Amino-5- (methoxyisopropyl 3.05(m, 2H), 3.19(m, 6H),methylisoxazole amino)isoxazole 2.92(m, 1H), 8.26(s, 1H) hydrochloridehydrochloride 22 5-Methyl-4-(N- 0.90(d, 3H), 2.35(s, 3H), 243 Meth 21methoxyisopropyl-N- 3.20(m, 8H), 3.60(s, 2H), methoxyacetamido) 4.80(m,1H), 8.40(m, 1H) isoxazole 23 5-Acetyl-1- 1.38(d, 3H), 2.40(s, 3H), 227Meth 22 methoxyisopropyl-2- 3.16(s, 3H), 3.24(s, 3H), methoxymethyl3.58(m, 1H), 3.78(m, 1H), imidazole 4.50(q, 2H), 4.96(m, 1H), 7.97(s,1H) 24 5-Methyl-4-(N- 0.81(t, 3H), 1.37(sext, 2H), 213 Meth 45 propyl-N-2.34(s, 3H), 3.18(s, 3H), methoxyacetamido) 3.42(t, 2H), 3.71(s, 2H),isoxazole 8.65(s, 1H) 25 1-Propyl-2- 0.83(t, 3H), 1.62(sext, 2H), 197Meth 24 methoxymethyl-5- 2.40(s, 3H), 3.25(s, 3H), acetylimidazole4.18(t, 2H), 4.50(s, 2H), 7.90(s, 1H) 26 5-Methyl-4-(N- 1.02(br m, 12H),2.32(m, 211 Meth 10 isopropyl-N-2- 1H), 2.37(s, 3H), 4.98(m,methylpropylamido)isoxazole 1H), 8.14(s, 1H) 27 1-Isopropyl-2- 1.38(d,6H), 1.55(d, 6H), 195 Meth 26 isopropyl-5- 2.43(s, 3H), 3.17(m, 1H),acetylimidazole 5.18(m, 1H), 7.78(s, 1H) 28 5-Methyl-4-[N-ethyl- 1.04(d,6H), 1.08(t, 3H), 197 Meth 16 N-(2-methylpropyl- 2.38(s, 3H), 2.41(m,1H), amido)]isoxazole 3.60(q, 2H), 8.15(s, 1H) 29 1-Ethyl-2-isopropyl-5-1.32(t, 3H), 1.34(d, 6H), 182 Meth 28 acetylimidazole 2.42(s, 3H),3.01(m, 1H), 4.36(q, 2H), 7.77(s, 1H) 30 5-Methyl-4-(N- 1.0(m, 9H),2.34(s, 3H), Meth 10 isopropyl-N- 3.34(m, 2H), 3.61(s, 2H),ethoxyacetamido) 4.73(m, 1H), 8.58(s, 1H) isoxazole 31 1-Isopropyl-2-1.10(t, 3H), 1.43(d, 6H), Meth 30 ethoxymethyl-5- 2.43(s, 3H), 3.44(m,2H), acetylimidazole 4.57(s, 2H), 4.96(m, 1H), 7.91(s, 1H) 325-Methyl-4-(N- 0.76(m, 4H), 1.42(m, 1H), 181 5-Methyl-4- methyl-N-2.36(s, 3H), 3.07(s, 3H), (methylamino)isoxazole cyclopropylamido)8.78(s, 1H) hydrochloride isoxazole 33 1-Methyl-2- 0.60(m, 4H), 1.72(m,1H), 165 Meth 32 cyclopropyl-5- 2.00(s, 3H), 3.55(s, 3H),acetylimidazole 7.41(s, 1H) 34 5-Methyl-4-(N- 0.80(m, 7H), 1.35(m, 3H),209 Meth 45 propyl-N- 2.32(s, 3H), 3.45(t, 2H), cyclopropylamido)8.76(s, 1H) isoxazole 35 1-Propyl-2- 0.80(m, 7H), 1.65(m, 2H), 193 Meth34 cyclopropyl-5- 2.05(m, 1H), 2.38(s, 3H), acetylimidazole 4.35(t, 2H),7.80(s, 1H) 36 5-Methyl-4-(N- 0.61(br s, 2H), 0.76(br s, 209 Meth 10isopropyl-N- 2H), 0.97(br s, 6H), cyclopropylamido) 1.24(m, 1H), 2.36(s,3H), isoxazole 4.76(m, 1H), 8.66(s, 1H) 37 1-Isopropyl-2- 0.96(m, 4H),1.49(d, 6H), 193 Meth 36 cyclopropyl-5- 2.11(m, 1H), 2.37(s, 3H),acetylimidazole 5.40(m, 1H), 7.77(s, 1H) 38 5-Methyl-4-(N-ethyl- 0.70(m,4H), 1.00(t, 3H), 195 Meth 16 N-cyclopropylamido) 1.36(m, 1H), 2.38(s,3H), isoxazole 3.54(q, 2H), 8.74(s, 1H) 39 1-Ethyl-2- 0.86(m, 2H),0.97(m, 2H), 179 Meth 38 cyclopropyl-5- 1.23(t, 3H), 2.04(m, 1H),acetylimidazole 2.36(s, 3H), 4.39(q, 2H), 7.78(s, 1H) 40 5-Methyl-4-(N-0.81(t, 3H), 1.37(m, 2H), 183 Meth 45 propyl-N-acetamido) 1.75(s, 3H),2.34(s, 3H), isoxazole 3.42(t, 2H), 8.67(s, 1H) 41 1-Propyl-2-methyl-5-0.83(t, 3H), 1.60(m, 2H), 167 Meth 40 acetylimidazole 2.37(m, 6H),4.17(t, 2H), 7.83(s, 1H) 42 5-Methyl-4-(N- Used crude Meth 10isopropylformido)isoxazole 43 5-Acetyl-1- 1.38(d, 6H), 2.48(s, 3H), 153Meth 42 isopropylimidazole 5.13(q, 2H), 7.86(s, 1H), 8.10(s, 1H) 445-Methyl-4-(N- 1.05(t, 3H), 2.28(q, 2H), 153[MH]− 4-amino-5-propylamido)isoxazole 2.35(s, 3H), 8.65(s, 1H), methylisoxazole 9.50(s,1H) hydrochloride 45 5-Methyl-4- 0.90(t, 3H), 1.62(m, 2H), 141 Meth 44(propylamino)isoxazole 2.53(s, 3H), 3.10(t, 2H), 8.68(s, 1H) 465-Methyl-4-(N- 1.05(t, 3H), 2.28(q, 2H), 153[MH]− 4-amino-5-propionylamido)isoxazole 2.35(s, 3H), 8.65(s, 1H), methylisoxazole9.50(s, 1H) hydrochloride 47 5-Methyl-4- 0.90(t, 3H), 1.62(m, 2H), 141Meth 46 (propylamino)isoxazole 2.53(s, 3H), 3.10(t, 2H), 8.68(s, 1H) 485-Methyl-4-(N- 0.82(m, 3H), 1.42(m, 2H), 167[MH]− Meth 47propylformido)isoxazole 2.28 & 2.38(s, 3H), 3.50(m, 2H), 8.08 & 8.23(2s,1H), 8.62 & 8.72(s, 1H) 49 5-Acetyl-1- 0.76(t, 3H), 1.63(m, 2H), 153Meth 48 propylimidazole 2.40(s, 3H), 4.28(t, 2H), 7.90(s, 1H), 7.95(s,1H)

Method 505-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole

1-Isopropyl-2-methoxymethyl-5-acetylimidazole (Method 12; 3.34 g, 17mmol) was dissolved in a mixture of DMF (34 ml) and DMF.DEA (11.5 ml, 68mmol) and the mixture heated under reflux, under an atmosphere ofnitrogen, for 18 hours. The volatiles were removed by evaporation. Asolid was precipitated with ether, collected by filtration and air driedto yield the title compound as a brown solid (2.25 g, 53%); NMR 1.43 (d,6H), 2.95 (m, 6H), 3.20 (s, 3H), 4.46 (s, 2H), 5.00 (m, 1H), 5.56 (d,1H), 7.55 (m, 2H); m/z 252.

Methods 51-68

The following compounds were prepared by the procedure of Method 50.

Meth Compound NMR M/z SM  51¹ 5-(3-Dimethylaminoprop-2-en-1- 2.87(s,3H), 3.05(s, 3H), 224 Meth 7 oyl)-1-methyl-2- 3.20(s, 3H), 3.83(s, 3H),4.45(s, methoxymethylimidazole 2H), 5.58(d, 1H), 7.55(d, 1H), 7.59(s,1H)  52² 5-(3-Dimethylaminoprop-2-en-1- 1.20(t, 3H), 2.62(q, 2H), 208Meth 9 oyl)-1-methyl-2-ethylimidazole 2.95(s, 6H), 3.78(s, 3H), 5.56(d,1H), 7.51(m, 2H)  53¹ 5-(3-Dimethylaminoprop-2-en-1- 1.20(d, 6H),3.05(m, 1H), 222 Meth oyl)-1-methyl-2-isopropylimidazole 3.80(s, 3H),5.53(d, 1H), 14 7.50(m, 2H) 54 5-(3-Dimethylaminoprop-2-en-1- 1.23(t,3H), 2.96(m, 6H), 222 Meth oyl)-1-ethyl-2- 3.25(s, 3H), 4.36(q, 2H), 18methoxymethylimidazole 4.47(s, 2H), 5.60(d, 1H), 7.56(d, 1H), 7.63(s,1H) 55 5-(3-Dimethylaminoprop-2-en-1- 1.20(m, 6H), 2.65(q, 2H), 238 Methoyl)-1,2-diethylimidazole 2.96(brs, 6H), 4.31(q, 2H), 20 5.57(d, 1H),7.51(d, 1H), 7.57(s, 1H) 56 5-(3-Dimethylaminoprop-2-en-1- 1.40(d, 3H),2.95(m, 6H), 282 Meth oyl)-1-methoxyisopropyl-2- 3.16(s, 3H), 3.24(s,3H), 23 methoxymethylimidazole 3.63(m, 1H), 3.89(m, 1H), 4.47(q, 2H),5.00(m, 1H), 5.58(d, 1H), 7.75(m, 2H) 57 5-(3-Dimethylaminoprop-2-en-1-2.26(s, 3H), 2.95(brs, 6H), 194 ³ oyl)-1,2-dimethylimidazole 3.8(s, 3H),5.56(d, 1H), 7.52(m, 2H) 58 5-(3-Dimethylaminoprop-2-en-1- 0.82(t, 3H),1.62(sext, 2H), 252 Meth oyl)-1-propyl-2- 2.7-3.3(br m, 6H), 3.24(s, 25methoxymethylimidazole 3H), 4.25(t, 2H), 4.45(s, 2H), 5.60(d, 1H),7.56(d, 1H), 7.60(s, 1H) 59 5-(3-Dimethylaminoprop-2-en-1- 1.37(d, 6H),1.58(d, 6H), 250 Meth oyl)-1-isopropyl-2- 2.94(s, 6H), 3.16(m, 1H), 27isopropylimidazole 5.23(m, 1H), 5.53(d, 1H), 7.50(s, 1H), 7.62(d, 1H) 605-(3-Dimethylaminoprop-2-en-1- 1.19(t, 3H), 1.21(d, 6H), 237 Methoyl)-1-ethyl-2-isopropylimidazole 2.48(s, 6H), 3.03(m, 1H), 4.33(q, 292H), 5.57(d, 1H), 7.55(d, 1H), 7.57(s, 1H) 615-(3-Dimethylaminoprop-2-en-1- 1.10(t, 3H), 1.28(d, 6H), 266 Methoyl)-1-isopropyl-2- 2.99(m, 6H), 3.41(m, 2H), 4.52(s, 31ethoxymethylimidazole 2H), 5.51(m, 1H), 5.59(d, 1H), 7.58(d, 2H) 625-(3-Dimethylaminoprop-2-en-1- 0.83(m, 2H), 0.94(m, 2H), Methoyl)-1-methyl-2- 1.97(m, 1H), 2.95(br s, 6H), 33 cyclopropylimidazole3.91(s, 3H), 5.55(d, 1H), 7.50(m, 2H) 63 5-(3-Dimethylaminoprop-2-en-1-0.80(m, 7H), 1.65(m, 2H), 248 Meth oyl)-1-propyl-2- 1.95(m, 1H), 2.95(brs, 6H), 35 cyclopropylimidazole 4.40(t, 2H), 5.55(d, 2H), 7.50(m, 2H) 645-(3-Dimethylaminoprop-2-en-1- 0.91(m, 4H), 1.49(d, 6H), 248 Methoyl)-1-isopropyl-2- 2.04(m, 1H), 2.93(m, 6H), 37 cyclopropylimidazole5.51(m, 2H), 7.40(s, 1H), 7.51(d, 1H) 65 5-(3-Dimethylaminoprop-2-en-1-0.88(m, 4H), 1.24(t, 3H), 234 Meth oyl)-1-ethyl-2- 1.99(m, 1H), 2.94(brs, 6H), 39 cyclopropylimidazole 4.47(q, 2H), 5.53(d, 1H), 7.51(m, 2H) 665-(3-Dimethylaminoprop-2-en-1- 0.82(t, 3H), 1.60(m, 2H), 222 Methoyl)-1-propyl-2-methylimidazole 2.32(s, 3H), 2.95(br s, 6H), 41 4.25(t,2H), 5.58(d, 1H), 7.54(d, 1H), 7.57(s, 1H) 675-(3-Dimethylaminoprop-2-en-1- 1.43(d, 6H), 2.95(m, 6H), Methoyl)-1-isopropylimidazole 5.32(m, 1H), 5.58(d, 1H), 43 7.60(m, 2H),7.90(s, 1H) 68 5-(3-Dimethylaminoprop-2-en-1- 0.75(t, 3H), 1.65(m, 2H),208 Meth oyl)-1-propylimidazole 2.95(br s, 6H), 4.25(t, 2H), 49 5.62(d,1H), 7.55(d, 1H), 7.64(s, 1H), 7.66(s, 1H) ¹DMF:DMF.DMA(1:1) used assolvent. Purified by flash chromatography on silica gel eluting withDCM/2% methanolic ammonia(100:0 increasing in polarity to 95:5).²DMF.DMA used as solvent ³Starting material(2-methyl-4-acetylimidazole)was synthesized according to Tetrahedron letters 1985, 26(29),3423-3426.

Method 692-Anilino-4-(1-isopropyl-2-methoxymethylimidazol-5-yl)pyrimidine

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole(Method 50; 1.26 g, 5 mmol), phenylguanidine hydrogen carbonate (1.09 g,5.5 mmol) and sodium methoxide (594 mg, 11 mmol) were suspended inanhydrous DMA (10 ml) and the mixture heated at 110° C. for 3 hours. Thevolatiles were evaporated in vacuo the residues was suspended in water(50 ml). The solution was extracted DCM (3×50 ml). The combined extractswere washed with water (50 ml) and then brine (50 ml), dried and thevolatiles removed by evaporation. The residue was purified by flashsilica chromatography eluting with DCM:MeOH (100:0 increasing inpolarity to 97:3) to give the title compound as brown oil. NMR: 1.43 (d,6H), 3.30 (s, 3H), 4.56 (s, 2H), 5.54 (m, 1H), 6.96 (t, 1H), 7.05 (d,1H), 7.24 (t,2H), 7.44 (s, 1H), 7.65 (d, 2H), 8.41 (d, 1H), 9.42 (s,1H); m/z 324.

Methods 70-84

The following compounds were prepared by the procedure of Method 69.

Meth Compound NMR M/z SM 70 2-Anilino-4-(1-methyl-2- 3.30(s, 3H) 3.99(s,3H), 296 Meth methoxymethylimidazol-5-yl) 4.50(s, 2H), 6.94(t, 1H),7.13(d, 51 pyrimidine 1H), 7.28(t, 2H), 7.65(s, 1H), 7.69(d, 2H),8.41(d, 1H), 9.48(s, 1H) 71 2-Anilino-4-(1-methyl-2- 1.36(d, 6H),3.08(m, 1H), 294 Meth isopropylimidazol-5-yl)pyrimidine 3.96(s, 3H),6.94(d, 1H), 53 7.05(t, 1H), 7.19(s, 1H), 7.37(t, 2H), 7.53(s, 1H),7.58(d, 2H), 8.36(d, 1H) 72 2-Anilino-4-(1-ethyl-2- 1.17(t, 3H), 3.28(s,3H), 310 Meth methoxymethylimidazol-5- 4.51(s, 2H), 4.60(q, 2H), 6.97(t,54 yl)pyrimidine 1H), 7.16(d, 1H), 7.29(t, 2H), 7.64(d, 2H), 7.71(s,1H), 8.40(d, 1H), 9.40(s, 1H) 73 2-Anilino-4-(1,2-diethylimidazol-1.15(t, 3H), 1.27(t, 3H), 294 Meth 5-yl)pyrimidine 2.72(q, 2H), 4.53(q,2H), 6.96(t, 55 1H), 7.11(d, 1H), 7.28(t, 2H), 7.64(m, 3H), 8.33(d, 1H),9.34(s, 1H) 74 2-Anilino-4-(1,2-dimethylimidazol- 2.37(s, 3H), 3.93(s,3H), 266 Meth 5-yl)pyrimidine 6.95(t, 1H), 7.08(d, 1H), 7.28(t, 57 2H),7.59(s, 1H), 7.69(d, 2H), 8.35(d, 1H), 9.43(s, 1H) 752-Anilino-4-(1-propyl-2- (400 MHz), 0.67(t, 3H), 324 Methmethoxymethylimidazol-5- 1.53(sext, 2H), 3.30(s, 3H), 58 yl)pyrimidine4.54(m, 4H), 7.00(t, 1H), 7.15(d, 1H), 7.32(t, 2H), 7.64(d, 2H), 7.70(s,1H), 8.42(d, 1H), 9.43(s, 1H) 76 2-Anilino-4-(1-isopropyl-2- 1.23(d,6H), 1.43(d, 6H), 323 Meth isopropylimidazol-5-yl)pyrimidine 3.22(m,1H), 5.61(m, 1H), 59 6.96(t, 1H), 7.01(d, 1H), 7.26(t, 2H), 7.42(s, 1H),7.64(d, 2H), 8.38(d, 1H), 9.39(br s, 1H) 77 2-Anilino-4-(1-ethyl-2-1.23(t, 3H), 1.38(d, 6H), 309 Meth isopropylimidazol-5-yl)pyrimidine3.05(m, 1H), 4.50(q, 2H), 6.94(d, 60 1H), 7.06(t, 1H), 7.34(t, 2H),7.56(d, 2H), 7.58(s, 1H), 8.32(d, 1H) 78 2-Anilino-4-(1-isopropyl-2-1.12(t, 3H), 1.46(d, 6H), 338 Meth ethoxymethylimidazol-5- 3.49(m, 2H),4.58(s, 2H), 5.54(m, 61 yl)pyrimidine 1H), 6.97(t, 1H), 7.06(d, 1H),7.28(t, 2H), 7.45(s, 1H), 7.66(d, 2H), 8.42(d, 1H), 9.43(s, 1H) 792-Anilino-4-(1-methyl-2- 0.83(m, 2H), 0.94(m, 2H), 292 Methcyclopropylimidazol-5- 2.08(m, 1H), 4.04(s, 3H), 62 yl)pyrimidine6.93(t, 1H), 7.09(d, 1H), 7.27(t, 2H), 7.51(s, 1H), 7.70(d, 2H), 8.38(d,1H), 9.40(s, 1H) 80 2-Anilino-4-(1-propyl-2- 0.70(t, 3H), 0.90(m, 4H),320 Meth cyclopropylimidazol-5- 1.55(m, 2H), 2.06(m, 1H), 63yl)pyrimidine 4.63(t, 2H), 6.93(t, 1H), 7.06(d, 1H), 7.27(t, 2H),7.56(s, 1H), 7.70(d, 2H), 8.32(d, 1H), 9.35(s, 1H) 812-Anilino-4-(1-isopropyl-2- 0.96(m, 4H), 1.53(d, 6H), 320 Methcyclopropylimidazol-5- 2.13(m, 1H), 5.80(m, 1H), 64 yl)pyrimidine6.99(m, 2H), 7.28(t, 2H), 7.37(s, 1H), 7.67(d, 2H), 8.36(d, 1H), 9.40(s,1H) 82 2-Anilino-4-(1-ethyl-2- 0.92(m, 4H), 1.23(t, 3H), 306 Methcyclopropylimidazol-5- 2.07(m, 1H), 4.69(q, 2H), 65 yl)pyrimidine6.98(t, 1H), 7.08(d, 1H), 7.29(t, 2H), 7.57(s, 1H), 7.65(d, 2H), 8.33(d,1H), 9.33(s, 1H) 83 2-Anilino-4-(1-propyl-2- 0.66(t, 3H), 1.51(m, 2H),294 Meth methylimidazol-5-yl)pyrimidine 2.39(s, 3H), 4.49(t, 2H), 666.99(t, 1H), 7.09(d, 1H), 7.62(s, 1H), 7.65(d, 2H), 8.36(d, 1H), 9.38(s,1H) 84 2-Anilino-4-(1-propylimidazol-5- 0.68(t, 3H), 1.55(m, 2H), 280Meth yl)pyrimidine 4.48(t, 2H), 6.97(t, 1H), 68 7.14(d, 1H), 7.30(t,2H), 7.63(d, 2H), 7.73(s, 1H), 7.88(s, 1H), 8.38(d, 1H), 9.40(s, 1H)

Method 852-Amino-4-(1-methoxyisopropyl-2-methoxymethylimidazol-5-yl)pyrimidine

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-methoxyisopropyl-2-methoxymethylimidazole(Method 56; 3.13, 11.1 mmol) and guanidine hydrochloride (2.65 g, 27.8mmol) were suspended in 1-butanol (20 ml). Sodium methoxide (2.4 g, 44mmol) was added in one portion and the mixture heated under reflux,under an atmosphere of nitrogen, for 18 hours. The volatiles wereremoved by evaporation. Water (50 ml) was added and extracted EtOAc(3×50 ml). The organic layers were combined and dried with ChemelutCE1010 and the solvent evaporated in vacuo. The residue was purified byflash silica chromatography eluting with DCM:MeOH (100:0 increasing inpolarity to 95:5) to give the title compound as an orange solid (1.86 g,60%). NMR: 1.43 (d, 3H), 3.16 (s, 3H), 3.24 (s, 3H), 3.63 (m, 1H), 3.89(m, 1H), 4.50 (q, 2H), 5.26 (m, 1H), 6.57 (s, 2H), 6.80 (d, 1H), 7.40(s, 1H), 8.21 (d, 1H); m/z 278.

Methods 86-88

The following compounds were prepared by the procedure of Method 85.

Meth Compound NMR M/z SM 86 2-Amino-4-(1-methyl-2- 1.21(t, 3H), 2.69(q,2H), 203 Meth ethylimidazol-5-yl)pyrimidine 3.92(s, 3H), 6.52(brs, 2H),6.81(d, 52 1H), 7.48(s, 1H), 8.15(d, 1H) 87 2-Amino-4-(1-propyl-2-0.82(t, 3H), 1.59(q, 2H), 218 Meth methylimidazol-5-yl)pyrimidine2.38(s, 3H), 4.42(t, 2H), 6.45(s, 66 2H), 6.82(d, 1H), 7.50(s, 1H),8.20(d, 1H) 88 2-Amino-4-(1- 1.53(d, 6H), 5.05(s, 2H), 204 Methisopropylimidazol-5- 5.59(sept, 1H), 6.85(d, 1H), 7.56(s, 67yl)pyrimidine 1H), 7.78(s, 1H), 8.23(d, 1H)

Method 89 2-Anilino-4-(1-methyl-2-n-butylimidazol-5-yl)pyrimidine

2-Anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 74; 2 g, 7.55mmol) was dissolved in anhydrous THF (100 ml) at RT under a nitrogenatmosphere. The stirring solution was cooled using dry-ice/acetone bathto −70° C. A 1.6M solution of n-butyl lithium in hexane (6.3 ml, 10.08mmol) was added drop-wise keeping temperature <−60° C. until the darkred colour remained. One more equivalent of n-butyl lithium in hexane(4.7 ml, 7.55 mmol), was then added dropwise keeping the temperaturebelow −60° C. At this point the solution stirred at −70° C. for 10minutes when propyl iodide (809 μl, 8.29 mmol) was added, thetemperature was maintained at −70° C. for an additional 10 minutes thenallowed to rise to RT. The reaction was allowed to stir for 1 hr at roomtemperature when water (100 ml) was added. The aqueous layer extractedwith EtOAc (2×20 ml). Organics were combined, dried solvent evaporatedin vacuo. The residue was purified by flash silica chromatographyDCM:MeOH (95:5) to yield the title compound (1.03 g, 45%) as a purewhite solid NMR: 0.90 (t, 3H), 1.39 (m, 2H), 1.66 (m, 2H), 2.70 (t, 2H),3.94 (s, 3H), 6.95 (t, 1H), 7.08 (d, 1H), 7.28 (t, 2H, 7.65 (d, 2H),7.59 (s, 1H), 8.35 (d, 1H), 9.42 (s, 1H); m/z 308.

Methods 90-102

The following compounds were prepared by the procedure of Method 89.

Meth Compound NMR M/z SM  90 2-Anilino-4-[1-methyl-2-(2- 0.9(s, 3H),2.65(m, 1H), 352 Pivaldehyde hydroxy-3,3-dimethylbutyl) 2.84(m, 1H),3.60(m, 1H), imidazol-5-yl]pyrimidine 3.98(s, 3H), 4.83(d, 1H), 6.97(t,1H), 7.10(d, 1H), 7.28(dd, 2H), 7.63(s, 1H), 7.71(d, 2H), 8.38(d, 1H),9.45(d, 1H)  91 2-Anilino-4-(1-methyl-2- 0.95(t, 3H), 1.70(m, 2H), 294Ethyl Iodide + Meth propylimidazol-5- 2.68(t, 2H), 3.92(s, 3H), 74yl)pyrimidine 6.95(t, 1H), 7.08(d, 1H), 7.28(t, 2H), 7.60(s, 1H),7.69(d, 2H), 8.34(d, 1H), 9.44(s, 1H)  92 2-Anilino-4-[1-methyl-2-(2-2.96(t, 2H), 3.26(s, 3H), 309 Chloromethyl- methoxyethyl)imidazol-5-3.70(t, 2H), 3.95(s, 3H), methylether + Meth yl]pyrimidine 6.94(t, 1H),7.09(s, 1H), 74 7.26(t, 2H), 7.60(s, 1H), 7.74(d, 2H), 8.38(s, 1H),9.44(s, 1H)  93 2-Anilino-4-(1-ethyl-2- 0.96(t, 3H), 1.15(t, 3H), 308Ethyl Iodide + Ex propylimidazol-5- 1.70(m, 2H), 2.68(t, 2H), 28yl)pyrimidine 4.54(q, 2H), 6.97(t, 1H), WO 7.10(d, 1H), 7.29(t, 2H),02/20512 7.65(m, 3H), 8.34(d, 1H), 9.35(s, 1H)  942-Anilino-4-(1-ethyl-2- 0.92(t, 3H), 1.14(t, 3H), 322 Propylbutylimidazol-5- 1.38(m, 2H), 1.68(m, 2H), Iodide + Ex yl)pyrimidine2.70(t, 2H), 4.56(q, 2H), 28 6.98(t, 1H), 7.08(d, 1H), WO 7.26(t, 2H),7.64(m, 3H), 02/20512 8.37(d, 1H), 9.36(s, 1H)  952-Anilino-4-(1-isopropyl-2- 1.98(t, 3H), 1.4(d, 6H), 322 Ethyl Iodide +Ex propylimidazol-5- 1.78(m, 2H), 2.76(t, 2H), 32 yl)pyrimidine 5.62(m,1H), 6.97(t, 1H), WO 7.02(d, 1H), 7.30(t, 2H), 02/20512 7.44(s, 1H),7.66(d, 2H), 8.39(d, 1H), 9.40(s, 1H)  96 2-Anilino-4-(1-isopropyl-2-1.26(t, 3H), 1.44(d, 6H), 308 Methyl ethylimidazol-5- 2.80(q, 2H),5.62(m, 1H), Iodide + Ex yl)pyrimidine 6.97(t, 1H), 7.02(d, 1H), 327.26(t, 2H), 7.42(s, 1H), WO 7.64(s, 2H), 8.39(d, 1H), 02/20512 9.39(s,1H)  97 2-Anilino-4-(1-methyl-2-(2- No NMR data 324 Acetone + Exmethyl-2- 5 WO hydroxypropyl)imidazol-5- 02/20512 yl)pyrimidine  982-{4-[N-(2-methoxyethyl)- 1.22-1.10(m, 18H), 2.82(s, 531 Acetone + MethN-(t-butyl)sulphamoyl] 2H), 3.28(s, 3H), 3.55-3.42(m, 107anilino}-4-(1-ethyl-2-(2- 4H), 4.79(q, 2H), methyl-2-hydroxypropyl)4.94(s, 1H), 7.22(d, 1H), 7.75-7.70(m, imidazol-5-yl)pyrimidine 3H),7.88(d, 2H), 8.42(d, 1H), 9.88(s, 1H).  99 2-Anilino-4-(1,2-dipropyl- NoNMR data 322 Ethyl iodide + Meth imidazol-5-yl)pyrimidine 83 1004-(2-But-3-enyl-1- No NMR data 601 Allyl propylimidazol-5-yl)-2-{4-bromide + Meth [N-(2-methoxyethyl)-N-(2- 108trimethylsilylethoxymethyl), sulphamoyl]anilino}pyrimidine  101¹4-[2-(3,3-Dimethyl-2- 0.64(t, 3H), 0.97(s, 9H), 380 Pivaldehyde + Methhydroxybut-1-yl)-1- 1.58-1.42(m, 2H), 3.59(s, 83(propyl)imidazol-5-yl]-2- 1H), 4.52-4.41(m, 1H), anilinopyrimidine4.63-4.58(m, 1H), 4.90(s, 1H), 6.99(t, 1H), 7.10(d, 1H), 7.30(t, 2H),7.63-7.60(m, 3H), 8.39(d, 2H), 9.39(s, 1H).  102¹ 4-{2-[2-(4- 3.02(s,4H), 3.90(s, 3H), 390 4- Chlorophenyl)ethyl]-1- 6.97(t, 1H), 7.09(d,1H), chlorobenzyl (methyl)imidazol-5-yl}-2- 7.30(m, 6H), 7.64(s, 1H),bromide + Meth anilinopyrimidine 7.70(d, 2H), 8.38(d, 1H), 74 9.42(s,1H) ¹Purified by chromatography on silica eluting with 2% MeOH/EtOAc

Method 1032-Anilino-4-(1-methyl-2-(3,3-dimethylbut-1-enylimidazol-5-yl)pyrimidine

2-Anilino-4-[1-methyl-2-(2-hydroxy-3,3-dimethylbutyl)imidazol-5-yl]pyrimidine(Method 90; 988 mg, 2.8 mmol) was dissolved in DCM (20 ml). To this wasadded triethylamine (1.18 ml, 8.4 mmol) followed by methanesulphonylchloride (458 μl, 5.92 mmol) in portions. After 18 hr the volatiles wereevaporated in vacuo and the residue resuspended in toluene (20 ml). Tothis stirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene(4 ml,26.7 mmol) and heated to reflux for 1 hr. Volatiles evaporated in vacuoand the residue was triturated with water. The resultant solid wascollected by filtration, washed water (20 ml) and dried under vacuum at60° C. to yield the title compound (830 mg, 90%). NMR 1.15 (s, 9H), 4.04(s, 3H), 6.38 (d, 1H), 6.8 (d, 1H), 6.96 (t, 1H), 7.12 (d, 1H), 7.28 (t,2H), 7.71 (m, 3H), 8.38 (d, 1H), 9.48 (s, 1H); m/z 334.

Method 1042-Anilino-4-[1-methyl-2-(3,3-dimethylbutylimidazol-5-yl]pyrimidine

To a solution of2-anilino-4-(1-methyl-2-(3,3-dimethylbut-1-enylimidazol-5-yl)pyrimidine(Method 103; 200 mg, 0.6 mmol) in EtOH (20 ml) was added 10% Pd/C (100mg) and stirred under a hydrogen atmosphere for 3 days. The reactionmixture was passed through a pad of celite to remove the catalyst andthe filtrate evaporated in vacuo. The residue was triturated with etherto give the title compound 105 mg (53%). NMR 0.97 (s, 9H), 1.60 (m, 2H),2.67 (m, 2H), 3.97 (s, 3H), 6.98 (t, 1H), 7.08 (d, 1H), 7.27 (dd, 2H),7.60 (s, 1H), 7.70 (d, 2H), 8.39 (d, 1H), 9.42 (s, 1H); m/z 336.

Method 1054-(2-Formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine

4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine(Method 106; 1.22 g, 2.33 mmol), was dissolved in anhydrous THF (70 ml),under nitrogen. The solution was cooled to −78° C. and n-butyl lithium(3.48 ml of a 1.6 N solution in hexanes, 5.57 mmol), was added slowly,maintaining the temperature at less than −65° C. The reaction mixturewas then stirred at −78° C. for 30 minutes, then DMF (345 μl, 4.46mmol), was added and mixture allowed to warm to ambient temperature andstirred for 1 hour. The reaction mixture was then poured into water (100ml), and extracted with EtOAc (2×50 ml). The organic extracts werecombined, washed with water (50 ml), brine (50 ml), and dried. Thevolatiles were removed and the residue was purified by chromatography onsilica gel eluting with 3% MeOH in DCM, to give the title product, (307mg, 24%), as a pale yellow foam. NMR: 0.02 (s, 9H), 0.83 (dd, 2H), 1.63(d, 6H), 3.28 (s, 3H), 3.37 (t, 2H), 3.42 (dd, 2H), 3.52 (t, 2H), 4.78(s, 2H), 5.71 (m, 1H), 7.40 (d, 1H), 7.82 (d, 2H), 7.92 (s, 1H), 8.01(d, 2H), 8.78 (d, 1H), 9.91 (s, 1H); m/z: 573 [MH]⁻.

Method 1064-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine

Sodium t-butoxide (1.42 g, 14.78 mmol), was added to a stirred solutionof 2-amino-4-(1-isopropylimidazol-5-yl)pyrimidine (Method 88; 2.0 g,9.85 mmol),N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl-4-iodobenzenesulphonamide(Method 112; 5.11 g, 10.84 mmol), tris(dibenzylideneacetone),dipalladium (0), (650 mg, 0.71 mmol), and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (470 mg, 0.75 mmol), indioxane (180 ml), and the mixture heated at 80° C. overnight. Thereaction was cooled to ambient temperature and acetic acid (282 μl, 4.93mmol), added. The reaction mixture was poured into water (70 ml), andextracted with EtOAc (3×40 ml). The organic extracts were combined,washed with water (2×40 ml), saturated brine (40 ml), dried, and thesolvent removed by evaporation. The residue was purified by flashchromatography on silica gel eluting with DCM/MeOH (97:3), and then bychromatography on silica gel eluting with DCM/MeOH (98.5:1.5), to yieldthe title compound (1.95 g, 36%). NMR: 0.01 (s, 9H), 085 (dd, 2H), 1.53(d, 6H), 3.26 (s, 2H), 3.37 (t, 2H), 3.44 (dd, 2H), 3.52 (t, 1H), 4.79(s, 2H), 5.57 (m, 1H), 7.36 (d, 1H), 8.80 (m, 3H), 7.98 (d, 2H), 8.19(s, 1H), 8.58 (d, 1H), 10.13 (s, 1H); m/z: 545 [MH]⁻.

Methods 107-108

The following compounds were prepared by an analogous procedure toMethod 106.

Meth Compound NMR M/z SM 107 4-(1-Ethyl-2- 1.15-1.22(m, 12H), 2.40(s,3H), 473 Meth 27 methylimidazol-5-yl)-2- 3.24-3.28(m, 3H), 3.46-3.55(m,WO {4-[N-(2-methoxyethyl)- 4H), 4.59(q, 2H), 7.20(d, 1H), 02/20512 +Meth N-t-butylsulphamoyl] 7.68(s, 1H), 7.70(d, 2H), 7.89(d, 113anilino}pyrimidine 2H), 8.42(d, 1H), 9.84(s, 1H) 108 4-(2-Methyl-1- NoNMR data 559 Meth 87 + Meth propylimidazol-5-yl)-2- [MH]⁻ 112{4-[N-(2-methoxyethyl)- N-(2-trimethylsilylethoxy methyl), sulphamoyl]anilino}pyrimidine

Method 1094-(1-Methyl-2-(2-methylpropyl)imidazol-5-yl)-2-anilinopyrimidine

4-(1-Methyl-2-(2-methylprop-1-enyl)imidazol-5-yl)-2-anilinopyrimidine(method 110; 400 mg, 1.3 mmol), and 10% Pd on C catalyst (150 mg), inethanol (50 ml), was hydrogenated at 40 C and 20 bar for 18 hours. Thecatalyst was removed by filtration and the filter pad washed withethanol. The solvent was evaporated and the residue triturated withether and collected by filtration to give the title compound (280 mg,71%). M/z: 308.

Method 1104-(1-Methyl-2-(2-methylprop-1-enyl)imidazol-5-yl)-2-anilinopyrimidine

Methanesulphonyl chloride (151 μl, 1.96 mmol), was added to a solutionof2-anilino-4-(1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl)pyrimidine(Method 97; 600 mg, 1.86 mmol), and triethylamine (777 μl, 5.58 mmol),in DCM (10 ml), at ambient temperature under nitrogen. The mixture wasstirred for 3 hours then adsorbed directly onto silica gel and purifiedby chromatography eluting with EtOAc to give the title compound (235 mg,42%). NMR: 1.98 (s, 3H), 2.14 (s, 3H), 3.99 (s, 3H), 6.24 (s, 1H), 6.98(t, 1H), 7.10 (d, 1H), 7.28 (dd, 2H), 7.69-7.72 (m, 3H), 8.40 (d, 1H),9.42 (s, 1H); m/z: 306.

Method 111

The following compounds were prepared by an analogous procedure toMethod 110.

Meth Compound M/z SM 1114-[2-(2-Methylprop-1-enyl)-1-ethylimidazol-5-yl]- 513 Meth2-{4-[N-(2-methoxyethyl)-N-t- 98 butylsulphamoyl]anilino}pyrimidine

Method 112N-(2-Methoxyethyl)-N-(2-trimethylsilylethoxymethyl)-4-iodobenzenesulphonamide

Sodium hydride (2.2 g, 55 mmol), was added to a solution ofN-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 4; 15.8 g, 46.3mmol), in DMF (250 ml), under nitrogen at 0° C. and the mixture stirredfor 1 hour. 2-Trimethylsilylethoxymethyl chloride (10 g, 60 mmol), wasadded and the mixture stirred overnight at ambient temperature. Thevolatiles were removed by evaporation and the residue dissolved inether, washed with water and then brine, dried (Na₂SO₄), and the solventevaporated to give the title compound (22.6 g, 74%). NMR: 0.2 (s, 9H),0.89 (t, 2H), 3.30 (s, 3H), 3.40-3.36 (m, 2H), 3.59-3.43 (m, 2H), 4.82(s, 2H), 7.60 (d, 2H), 7.84 (d, 2H).

Method 113 N-(2-Methoxyethyl)-N-(t-butyl)-4-iodobenzenesulphonamide

Sodium hydride (71 mg, 1.77 mg), was added to a solution ofN-t-butyl-4-iodobenzenesulphonamide (Method 5; 500 mg, 1.47 mmol), inanhydrous DMF (15 ml), under nitrogen at 0° C. The resulting suspensionwas stirred at 0° C. for 30 minutes. A solution of1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg,1.77 mmol), in DMF (15 ml), (pre-stirred at ambient temperature for 1hr), was then added dropwise to the mixture while the, reactiontemperature was maintained at 0° C. and the mixture stirred for 10minutes. The mixture was allowed to warm to ambient temperature, andthen heated at 60° C. for 20 hours. A further solution of1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg,1.77 mmol), in DMF (15 ml), (pre-stirred at ambient temperature for 1hr), was then added dropwise to the mixture at ambient temperature andthe reaction mixture was heated at 60° C. for 20 hours. The mixture wascooled and solvent removed by evaporation. The residue was dissolved inether (25 ml), washed with 10% aqueous sodium hydroxide solution (20ml), water (3×25 ml), and dried. The volatiles were removed byevaporation and the residue purified by flash chromatography on silicagel eluting with DCM to yield the title product as a clear oil thatcrystallised on standing (147 mg, 25%), NMR: 1.23 (s, 9H), 3.24 (s, 3H),3.48 (s, 4H), 7.57 (d, 2H), 7.94 (d, 2H).

Method 1144-[2-(3,3-Dimethylbut-1-en-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine

Triethylamine (0.74 ml, 5.05 mmol), followed by methane sulphonylchloride (0.103 ml, 1.33 mmol) was added to a stirred solution of4-[2-(3,3-dimethyl-2-hydroxybut-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine(Method 101; 480 mg, 1.26 mmol) in DCM (40 ml) at ambient temperatureand the mixture stirred for 24 hours. The volatiles were removed byevaporation and toluene (10 ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.38 ml, 2.54 mmol) was added to the residue. The mixture was heated atreflux for 5 hours, allowed to cool, washed with water and extractedwith EtOAc. The extracts were combined, dried and the solvent removed byevaporation to give the title compound (240 mg, 53%). NMR: 0.64 (t, 3H),1.15 (s, 9H), 1.53 (q, 2H), 4.64 (t, 2H), 6.38 (d, 1H), 6.80 (d, 1H),6.99 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (d, 3H), 7.75 (s, 1H),8.38 (d, 1H), 9.38 (s, 1H); m/z 362.

Method 1154-[2-(3,3-Dimethylbutyl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine

A mixture of 10% palladium on charcoal catalyst (100 mg),4-[2-(3,3-dimethylbut-1-en-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine(Method 114; 230 mg, 0.64 mmol) in ethanol (50 ml) was stirred under anatmosphere of hydrogen for 72 hours. The catalyst was removed byfiltration through diatomaceous earth, and the filter pad washed withwarm MeOH. The solvent removed by evaporation to give the title compound(200 mg, 86%). M/z 364.

Method 1164-[2-(Chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (2.29 g, 20 mmol) was added dropwise to a stirredsolution of2-anilino-4-(1-propyl-2-methoxymethylimidazol-5-yl)pyrimidine (Method75; 1.29 g, 4.0 mmol) in thionyl chloride (30 ml), cooled to 0-4° C. Thesolution was allowed to warm to ambient temperature and was then heatedunder reflux for 18 hour. The mixture was cooled and an oil separatedout. The excess thionyl chloride was decanted from this oil, and theresidue was washed with thionyl chloride (10 ml) and any volatilesremoved by evaporation. The residue was dissolved in MeOH (15 ml),cooled to 0-4° C. and a solution of 2-ethoxyethylamine (3.56 g, 40 mmol)in cold MeOH (15 ml) was added. The reaction mixture was allowed to warmto ambient temperature and stirred for one hour. The mixture was allowedto stand and cooled to 0-4° C. The resulting crystalline product wascollected by filtration, washed with MeOH and dried to give the titlecompound (587 mg, 31%). NMR: 0.70 (t, 3H), 1.05 (t, 3H), 1.55 (m, 2H),2.86 (m, 2H), 3.33 (m, 4H), 4.60 (t, 2H), 4.95 (s, 2H), 7.25 (d, 1H),7.46 (t, 1H), 7.71 (d, 2H), 7.75 (s, 1H), 7.86 (d, 2H), 8.50 (d, 1H),9.90 (s, 1H); m/z 479.

Method 1174-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-anilinopyrimidine(Method 102) was treated with 2-methoxyethylamine by the conditionsdescribed in Method 116. The crude product was purified bychromatography on silica gel eluting with DCM/MeOH (98:2) to give thetitle compound (164 mg, 48%) as glassy solid. NMR: 2.88 (q, 2H), 3.02(s, 4H), 3.15 (s, 3H), 3.26 (m, 2H), 3.92 (s, 3H), 7.21 (d, 1H), 7.32(d, 4H), 7.44 (s, 1H), 7.66 (s, 1H), 7.68 (d, 2H), 7.90 (d, 2H), 8.44(d, 1H), 9.92 (s, 1H); m/z 528.

Method 118 2-Anilino-4-(2-formyl-1-propylimidazol-5-yl)pyrimidine

2-Anilino-4-(1-propylimidazol-5-yl)pyrimidine (Method 84) was treated asdescribed in Method 105. The crude product was purified bychromatography on silica gel eluting with EA/IsoHex) (80:20) to give thetitle compound (1.051 g, 48%) as a yellow solid. NMR: 0.63 (t, 3H), 1.59(m, 2H), 4.94 (t, 2H), 7.01 (t, 1H), 7.30 (m, 3H), 7.63 (d, 2H), 8.0 (s,1H), 8.55 (d, 1H), 9.60 (s, 1H), 9.80 (s, 1H).

Method 1192-Anilino-4-(2-dimethylaminomethyl-1-propylimidazol-5-yl)pyrimidine

A mixture of 2-anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine(Method 118; 200 mg, 0.65 mmol) and dimethylamine (391 μl of 2M solutionin THF, 0.78 mmol) in MeOH (6 ml) stirred for 3 hours at ambienttemperature. Acetic acid (41 mg, 0.716 mmol) and sodium cyanoborohydride(45 mg, 0.716 mmol) were added and the mixture stirred for a further 18hours. The volatiles were removed by evaporation and residue dissolvedin EtOAc (7 ml). This solution was washed with saturated aqueous sodiumhydrogen carbonate solution, water, and brine, then dried and thesolvent removed by evaporation to give the title compound (210 mg, 96%)as a yellow foam. NMR: 0.62 (t, 6H), 1.50 (m, 2H), 2.23 (s, 6H), 3.60(s, 2H), 4.56 (m, 2H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62(m, 3H), 8.39 (d, 1H), 9.39 (s, 1H); m/z 337.

Method 120 2-Anilino4-(2-ethylamniomethyl-1-propylimidazol-5-yl)pyrimidine

2-Anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine (Method 118) wastreated with ethylamine (2M solution in MeOH) by the procedure of Method119 to give the title compound (185 mg, 93%) as a yellow foam. M/z 337.

Example 87

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof (hereafter compound X), fortherapeutic or prophylactic use in humans:—

(a): Tablet I mg/tablet Compound X 100 Lactose Ph•Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0

(b): Tablet II mg/tablet Compound X 50 Lactose Ph•Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0

(c): Tablet III mg/tablet Compound X 1.0 Lactose Ph•Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0

(d): Capsule mg/capsule Compound X 10 Lactose Ph•Eur 488.5 Magnesiumstearate 1.5

(e): Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodium hydroxidesolution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100%

(f): Injection II 10 mg/ml Compound X 1.0% w/v Sodium phosphate BP 3.6%w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100%

(g): Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

1. A compound of formula (I):

wherein: R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy; p is 0-2; whereinthe values of R¹ may be the same or different; R² is C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl, aheterocyclyl or heterocyclylC₁₋₃ alkyl; wherein R₂ may be optionallysubstituted on carbon by one or more methyl, ethyl, methoxy, ethoxy,propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy orcyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by one or moremethyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl; R³ ishydrogen, halo or cyano; R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl; R⁵ issubstituted methyl, optionally substituted C₂₋₆alkyl, or optionallysubstituted C₂₋₆alkenyl; wherein said substituents are selected from oneor more methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy,2,2,2-trifluoroethoxy or cyclopropylmethoxy; or a pharmaceuticallyacceptable salt thereof; provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.
 2. A compound of formula (I) according toclaim 1 wherein p is 0; or a pharmaceutically acceptable salt thereof.3. A compound of formula (I) according to claim 1 wherein R² isC₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl orheterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy, ethoxy or trifluoromethyl; or apharmaceutically acceptable salt thereof.
 4. A compound of formula (I)according to claim 1 wherein R³ is hydrogen; or a pharmaceuticallyacceptable salt thereof.
 5. The compound of formula (I) according toclaim 1 wherein R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; or apharmaceutically acceptable salt thereof.
 6. The compound of formula (I)according to claim 1 wherein R⁵ is substituted methyl, or optionallysubstituted C₂₋₆alkyl; wherein said substituents are selected from oneor more methoxy; or a pharmaceutically acceptable salt thereof.
 7. Acompound of formula (I) as depicted in claim 1 wherein: p is 0; R² is2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl,t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl ortetrahydrofur-2-ylmethyl; R³ is hydrogen; R⁴ is methyl, ethyl, isopropylor 1-methoxyprop-2-yl; or R⁵ is methoxymethyl, isopropyl, ethyl, butylor 3,3-dimethylbutyl; or a pharmaceutically acceptable salt thereof;provided that the compound is not4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine;4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine;4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine;or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.
 8. A compound of formula (I) as depictedin claim 1 selected from:4-(1,2-diethylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine;4-(1,2-diethylimidazol-5-yl)-2-{4-[N-(cyclopropyl)sulphamoyl]anilino}pyrimidine;and4-(1,2-diethylimidazol-5-yl)-2-{4-[N-(allyl)sulphamoyl]anilino}pyrimidine;or a pharmaceutically acceptable salt thereof.
 9. A process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof as claimed in claim 1, which process (wherein R¹, R², R³,R⁴, R⁵ and p are, unless otherwise specified, as defined in claim 1)comprises of: Process a) reaction of a pyrimidine of formula (II):

wherein L is a displaceable group; with an aniline of formula (III):

Process b) reacting a compound of formula (IV):

with a compound of formula (V):

wherein T is O or S; R^(x) may be the same or different and isC₁₋₆alkyl; Process c) reacting a pyrimidine of formula (VI):

wherein X is a displaceable group; with an amine of formula (VII):R²—NH₂  (VII) or Process d) reacting a pyrimidine of formula (VIII)

with a compound of formula (IX):

where Y is a displaceable group; and thereafter if necessary: i)converting a compound of the formula (I) into another compound of theformula (I); ii) removing any protecting groups; iii) forming apharmaceutically acceptable salt.
 10. A pharmaceutical composition whichcomprises a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof, according to claim 1, in association with apharmaceutically-acceptable diluent or carrier.
 11. A method fortreating rheumatoid arthritis in a warm-blooded animal in need thereof,which comprises administering to said animal an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof asclaimed in claim 1.